Trial Outcomes & Findings for Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa (NCT NCT02021318)

NCT ID: NCT02021318

Last Updated: 2024-11-14

Results Overview

Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb \> 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell \[RBC\] transfusion for all participants or darbepoetin for roxadustat treated participant).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 616 participants
• Primary outcome timeframe: Baseline to week 24
• Results posted on: 2024-11-14

Participant Flow

Participants of ≥ 18 years of age with a diagnosis of chronic kidney disease, with kidney disease outcomes quality initiative stage 3, 4 or 5, anaemic and not receiving dialysis; with an estimated glomerular filtration rate (eGFR) < 60 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) were enrolled in this study.

Participants were randomized in a 1:1 ratio to roxadustat or darbepoetin alfa. Randomization was stratified by 4 factors: region, screening hemoglobin (Hb) values (Hb ≤ 8.0 g/dL versus > 8.0 g/dL), history of cardiovascular, cerebrovascular or thromboembolic diseases and screening eGFR (<30 mL/min/1.73 m^2 versus ≥30 mL/min/1.73 m^2 ).

Participant milestones

Measure	Roxadustat Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 milligram (mg) given three times weekly (TIW) to participants weighing between 45 kilogram (kg) up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 microgram per kilogram \[μg/kg\] of body weight, as a single subcutaneous or intravenous \[IV\] injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 grams per deciliter (g/dL) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Overall Study STARTED	323	293
Overall Study COMPLETED	250	230
Overall Study NOT COMPLETED	73	63

Reasons for withdrawal

Measure	Roxadustat Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 milligram (mg) given three times weekly (TIW) to participants weighing between 45 kilogram (kg) up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 microgram per kilogram \[μg/kg\] of body weight, as a single subcutaneous or intravenous \[IV\] injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 grams per deciliter (g/dL) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Overall Study Adverse Event	2	1
Overall Study Death	33	34
Overall Study Lost to Follow-up	3	3
Overall Study Progressive Disease	0	1
Overall Study Withdrawal by Subject	30	18
Overall Study Physician Decision	3	3
Overall Study Miscellaneous	2	3

Baseline Characteristics

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa

Baseline characteristics by cohort

Measure	Roxadustat n=323 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=293 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.	Total n=616 Participants Total of all reporting groups
Age, Continuous	66.8 Years STANDARD_DEVIATION 13.6 • n=5 Participants	65.7 Years STANDARD_DEVIATION 14.4 • n=7 Participants	66.3 Years STANDARD_DEVIATION 14 • n=5 Participants
Sex: Female, Male Female	178 Participants n=5 Participants	164 Participants n=7 Participants	342 Participants n=5 Participants
Sex: Female, Male Male	145 Participants n=5 Participants	129 Participants n=7 Participants	274 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	8 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	306 Participants n=5 Participants	281 Participants n=7 Participants	587 Participants n=5 Participants
Baseline Hb Value <=8.0 g/dL	11 Participants n=5 Participants	10 Participants n=7 Participants	21 Participants n=5 Participants
Baseline Hb Value >8.0 g/dL	312 Participants n=5 Participants	283 Participants n=7 Participants	595 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to week 24

Population: The analysis population was the Per Protocol Set (PPS) which consisted of all Full Analysis Set (FAS) participants who did not meet any of exclusion criteria from the PPS. The FAS consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose valid Hb assessment.

Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell [RBC] transfusion for all participants or darbepoetin for roxadustat treated participant).

Outcome measures

Measure	Roxadustat n=286 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=273 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy	89.5 Percentage of Participants	78.0 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 28 to 36

Population: The analysis population was the PPS, with participants who had available data.

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Outcome measures

Measure	Roxadustat n=258 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=249 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period	1.848 g/dL Standard Deviation 1.079	1.839 g/dL Standard Deviation 0.973

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, with participants who had available data.

Baseline LDL-C was defined as the LDL-C value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Outcome measures

Measure	Roxadustat n=307 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=277 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28	-0.352 Millimoles per liter (mmol/L) Standard Deviation 0.772	0.049 Millimoles per liter (mmol/L) Standard Deviation 0.705

SECONDARY outcome

Timeframe: Weeks 6, 12, 18, 24, 30 and 36

Population: The analysis population was the FAS.

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one intravenous iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Intravenous Iron Use Week 6	0 Percentage of participants Interval 0.0 to 0.0	2.8 Percentage of participants Interval 0.9 to 4.6
Time to First Intravenous Iron Use Week 12	1.3 Percentage of participants Interval 0.0 to 2.5	6.7 Percentage of participants Interval 3.8 to 9.6
Time to First Intravenous Iron Use Week 18	3.3 Percentage of participants Interval 1.3 to 5.2	9.2 Percentage of participants Interval 5.8 to 12.6
Time to First Intravenous Iron Use Week 24	4.3 Percentage of participants Interval 2.0 to 6.5	10.7 Percentage of participants Interval 7.1 to 14.3
Time to First Intravenous Iron Use Week 30	5.3 Percentage of participants Interval 2.8 to 7.8	12.6 Percentage of participants Interval 8.7 to 16.5
Time to First Intravenous Iron Use Week 36	6.7 Percentage of participants Interval 3.9 to 9.6	13.3 Percentage of participants Interval 9.3 to 17.3

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the PPS, with participants who had available data.

Baseline SF-36 PF was defined as the SF-36 PF value on Day 1.The SF-36 is a Quality of Life (QoL) instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consisted of 11 questions that focused on health and ability to do usual activities, with higher scores indicating better health status.

Outcome measures

Measure	Roxadustat n=274 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=256 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub Score in Weeks 12 to 28	0.913 Units on a scale Standard Deviation 7.182	2.062 Units on a scale Standard Deviation 7.838

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the PPS, with participants who had available data.

Baseline VT Subscore was defined as the VT value on Day 1. The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 vitality has four questions with score range from 0-100 with higher scores indicating better vitality status.

Outcome measures

Measure	Roxadustat n=274 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=256 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28	4.077 Units on a scale Standard Deviation 8.657	3.881 Units on a scale Standard Deviation 8.76

SECONDARY outcome

Timeframe: Baseline and weeks 20 to 28

Population: The analysis population was the PPS, with participants who had available data.

Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*diastolic blood pressure (DBP) + (1/3)*systolic blood pressure (SBP).

Outcome measures

Measure	Roxadustat n=265 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=252 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set	0.541 Millimeters of mercury (mmHg) Standard Deviation 8.549	0.588 Millimeters of mercury (mmHg) Standard Deviation 8.779

SECONDARY outcome

Timeframe: Weeks 1 to 36

Population: The analysis population was the PPS.

Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=286 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=273 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set	17.5 Percentage of Participants	19.4 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 20 to 28

Population: The analysis population was the FAS, with participants who had available data.

Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*DBP + (1/3)*SBP.

Outcome measures

Measure	Roxadustat n=294 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=269 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set	0.635 mmHg Standard Deviation 8.529	0.457 mmHg Standard Deviation 8.741

SECONDARY outcome

Timeframe: Weeks 1 to 36

Population: The analysis population was the FAS.

Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set	17.4 Percentage of Participants	18.8 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 28 to 52

Population: The analysis population was the FAS, with participants who had available data.

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).

Outcome measures

Measure	Roxadustat n=287 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=266 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless of Rescue Therapy	1.718 g/dL Standard Deviation 0.958	1.673 g/dL Standard Deviation 0.923

SECONDARY outcome

Timeframe: Weeks 1 to 24

Population: The analysis population was the FAS.

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy	88.8 Percentage of Participants	77.7 Percentage of Participants

SECONDARY outcome

Timeframe: Weeks 1 to 24

Population: The analysis population was the FAS.

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy	88.2 Percentage of participants	77.4 Percentage of participants

SECONDARY outcome

Timeframe: Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

Population: The analysis population was the FAS.

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy Weeks 28-36	11.403 g/dL Interval 11.302 to 11.503	11.351 g/dL Interval 11.247 to 11.455
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy Weeks 44-52	11.185 g/dL Interval 11.082 to 11.289	11.188 g/dL Interval 11.082 to 11.294
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy Weeks 72-80	11.225 g/dL Interval 11.12 to 11.331	11.217 g/dL Interval 11.11 to 11.324
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy Weeks 96-104	11.102 g/dL Interval 10.986 to 11.219	11.078 g/dL Interval 10.96 to 11.196

SECONDARY outcome

Timeframe: Baseline and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104

Population: The analysis population was the FAS.

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 12	2.33 g/dL Interval 2.204 to 2.456	2.03 g/dL Interval 1.897 to 2.162
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 14	1.904 g/dL Interval 1.781 to 2.027	1.745 g/dL Interval 1.616 to 1.875
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 1	0.381 g/dL Interval 0.311 to 0.45	0.294 g/dL Interval 0.221 to 0.368
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 2	0.862 g/dL Interval 0.782 to 0.941	0.584 g/dL Interval 0.5 to 0.667
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 4	1.508 g/dL Interval 1.403 to 1.613	1.073 g/dL Interval 0.962 to 1.183
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 6	1.845 g/dL Interval 1.729 to 1.962	1.423 g/dL Interval 1.3 to 1.546
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 8	2.063 g/dL Interval 1.94 to 2.185	1.682 g/dL Interval 1.554 to 1.81
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 10	1.941 g/dL Interval 1.819 to 2.062	1.611 g/dL Interval 1.483 to 1.739
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 16	2.177 g/dL Interval 2.053 to 2.301	1.994 g/dL Interval 1.864 to 2.124
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 18	1.783 g/dL Interval 1.669 to 1.896	1.609 g/dL Interval 1.49 to 1.729
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 20	1.986 g/dL Interval 1.869 to 2.103	1.9 g/dL Interval 1.778 to 2.023
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 22	1.584 g/dL Interval 1.473 to 1.696	1.615 g/dL Interval 1.499 to 1.731
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 24	1.493 g/dL Interval 1.383 to 1.603	1.554 g/dL Interval 1.438 to 1.669
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 28	1.803 g/dL Interval 1.688 to 1.919	1.869 g/dL Interval 1.748 to 1.989
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 32	1.687 g/dL Interval 1.568 to 1.806	1.673 g/dL Interval 1.549 to 1.797
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to Week 36	1.913 g/dL Interval 1.793 to 2.032	1.781 g/dL Interval 1.657 to 1.905
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 40	1.625 g/dL Interval 1.51 to 1.74	1.438 g/dL Interval 1.32 to 1.556
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 44	1.65 g/dL Interval 1.527 to 1.773	1.628 g/dL Interval 1.502 to 1.754
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 48	1.459 g/dL Interval 1.338 to 1.581	1.447 g/dL Interval 1.322 to 1.572
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 52	1.682 g/dL Interval 1.56 to 1.803	1.71 g/dL Interval 1.585 to 1.835
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 56	1.412 g/dL Interval 1.292 to 1.533	1.444 g/dL Interval 1.321 to 1.567
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 60	1.735 g/dL Interval 1.611 to 1.859	1.67 g/dL Interval 1.543 to 1.796
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 64	1.546 g/dL Interval 1.415 to 1.676	1.547 g/dL Interval 1.414 to 1.681
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 68	1.851 g/dL Interval 1.726 to 1.976	1.747 g/dL Interval 1.62 to 1.875
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 72	1.615 g/dL Interval 1.486 to 1.745	1.548 g/dL Interval 1.416 to 1.68
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 76	1.745 g/dL Interval 1.616 to 1.873	1.767 g/dL Interval 1.636 to 1.898
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 80	1.534 g/dL Interval 1.408 to 1.661	1.579 g/dL Interval 1.451 to 1.707
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 84	1.723 g/dL Interval 1.594 to 1.853	1.679 g/dL Interval 1.548 to 1.809
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 88	1.424 g/dL Interval 1.291 to 1.557	1.37 g/dL Interval 1.236 to 1.504
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 92	1.677 g/dL Interval 1.541 to 1.812	1.643 g/dL Interval 1.505 to 1.78
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 96	1.429 g/dL Interval 1.293 to 1.566	1.404 g/dL Interval 1.266 to 1.542
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 100	1.488 g/dL Interval 1.346 to 1.629	1.598 g/dL Interval 1.454 to 1.742
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy Hb Change From BL to week 104	1.489 g/dL Interval 1.339 to 1.64	1.452 g/dL Interval 1.299 to 1.606

SECONDARY outcome

Timeframe: Baseline and weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

Population: The analysis population was the FAS.

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy Hb Change From BL to weeks 28-36	1.825 g/dL Interval 1.723 to 1.926	1.799 g/dL Interval 1.694 to 1.905
Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy Hb Change From BL to weeks 44-52	1.619 g/dL Interval 1.513 to 1.724	1.62 g/dL Interval 1.512 to 1.729
Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy Hb Change From BL to weeks 72-80	1.652 g/dL Interval 1.545 to 1.759	1.649 g/dL Interval 1.54 to 1.758
Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy Hb Change From BL to weeks 96-104	1.486 g/dL Interval 1.363 to 1.608	1.502 g/dL Interval 1.378 to 1.626

SECONDARY outcome

Timeframe: Weeks 28 to 36, 44 to 52 and 96 to 104

Population: The analysis population was the FAS.

Percentage for each participant was calculated from the number of Hb values within 10.0-12.0 g/dL / total number of Hb values*100 in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 96-104, >= 10	90.436 Percentage of Hb values Standard Deviation 22.725	87.777 Percentage of Hb values Standard Deviation 27.03
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 28-36, >= 10	93.078 Percentage of Hb values Standard Deviation 20.671	92.481 Percentage of Hb values Standard Deviation 19.876
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 28-36, Within 10-12	67.896 Percentage of Hb values Standard Deviation 33.499	69.217 Percentage of Hb values Standard Deviation 34.171
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 44-52, >= 10	90.921 Percentage of Hb values Standard Deviation 23.123	89.416 Percentage of Hb values Standard Deviation 24.833
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 44-52, Within 10-12	74.104 Percentage of Hb values Standard Deviation 32.119	68.931 Percentage of Hb values Standard Deviation 35.367
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 72-80, >= 10	91.494 Percentage of Hb values Standard Deviation 20.923	90.343 Percentage of Hb values Standard Deviation 24.364
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 72-80, Within 10-12	69.71 Percentage of Hb values Standard Deviation 32.444	67.861 Percentage of Hb values Standard Deviation 37.024
Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 96-104, Within 10-12	72.393 Percentage of Hb values Standard Deviation 33.277	68.629 Percentage of Hb values Standard Deviation 35.352

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks Year 0.5	45.5 Percentage of participants Interval 40.0 to 51.0	28.9 Percentage of participants Interval 23.6 to 34.1
Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks Year 1	48.8 Percentage of participants Interval 43.2 to 54.4	30.9 Percentage of participants Interval 25.4 to 36.3
Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks Year 1.5	53.4 Percentage of participants Interval 47.7 to 59.1	35 Percentage of participants Interval 29.3 to 40.7
Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks Year 2	55.3 Percentage of participants Interval 49.5 to 61.0	37.8 Percentage of participants Interval 31.9 to 43.7

SECONDARY outcome

Timeframe: Baseline to EOT (up to week 104)

Population: The analysis population was the FAS.

The number of hospitalizations per participant were calculated during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Hospitalizations	1.5 Hospitalizations Standard Deviation 2.4	1.4 Hospitalizations Standard Deviation 2.3

SECONDARY outcome

Timeframe: Baseline to EOT (up to week 104)

Population: The analysis population was the FAS.

The number of days of hospitalization per year was calculated as the sum of the durations of all hospitalizations in days (minimum [date of discharge, end of efficacy of emergent period] - date of admission + 1) / (duration of efficacy emergent period in days / 365.25). The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Days of Hospitalization Per Year	12.6 Days per year Standard Deviation 22	11.3 Days per year Standard Deviation 27.7

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

Time to first hospitalization in years was defined in years as: (first event date during the efficacy emergent period - analysis date of first dose intake +1)/365.25, and the 'first event date' was defined as 'date of first admission and 'analysis date of first dose intake. Date of end of efficacy emergent period was defined as as the treatment period up to the EOT visit. For participants who have experienced more than one hospitalization, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Hospitalization Year 0.5	31.7 Percentage of participants Interval 26.5 to 36.8	21.8 Percentage of participants Interval 17.0 to 26.7
Time to First Hospitalization Year 1	43.7 Percentage of participants Interval 38.2 to 49.3	40.4 Percentage of participants Interval 34.6 to 46.2
Time to First Hospitalization Year 1.5	55.2 Percentage of participants Interval 49.6 to 60.9	50.2 Percentage of participants Interval 44.2 to 56.1
Time to First Hospitalization Year 2	62.3 Percentage of participants Interval 56.7 to 67.9	56.7 Percentage of participants Interval 50.7 to 62.7

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one RBC transfusion, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Use of RBC Transfusion Year 0.5	3 Percentage of participants Interval 1.1 to 4.9	2.1 Percentage of participants Interval 0.4 to 3.8
Time to First Use of RBC Transfusion Year 1	7.3 Percentage of participants Interval 4.3 to 10.3	6.5 Percentage of participants Interval 3.5 to 9.5
Time to First Use of RBC Transfusion Year 1.5	10.9 Percentage of participants Interval 7.2 to 14.6	9.4 Percentage of participants Interval 5.8 to 13.0
Time to First Use of RBC Transfusion Year 2	13.9 Percentage of participants Interval 9.7 to 18.2	11.2 Percentage of participants Interval 7.3 to 15.1

SECONDARY outcome

Timeframe: Baseline to EOT (up to week 104)

Population: The analysis population was the FAS.

The number of RBC packs were calculated as the sum of units transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their number of RBC packs set to 0.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of RBC Packs	0.4 RBC packs Standard Deviation 1.20	0.4 RBC packs Standard Deviation 1.98

SECONDARY outcome

Timeframe: Baseline to EOT (up to week 104)

Population: The analysis population was the FAS.

The volume of blood transfused was calculated as the sum of blood volume transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their volume set to 0.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Volume of RBC Transfused	97.0 mL Standard Deviation 112.2	334.63 mL Standard Deviation 508.40

SECONDARY outcome

Timeframe: Baseline to EOT (up to week 104)

Population: The analysis population was the FAS.

Participants who received RBC transfusions during the efficacy emergent period were reported. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Particpants Who Received RBC Transfusions	38 Participants	28 Participants

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Use of Rescue Therapy Year 0.5	4 Percentage of participants Interval 1.8 to 6.2	2.1 Percentage of participants Interval 0.4 to 3.8
Time to First Use of Rescue Therapy Year 1	9.3 Percentage of participants Interval 6.0 to 12.7	6.5 Percentage of participants Interval 3.5 to 9.5
Time to First Use of Rescue Therapy Year 1.5	13.3 Percentage of participants Interval 9.3 to 17.3	9.4 Percentage of participants Interval 5.8 to 13.0
Time to First Use of Rescue Therapy Year 2	16.7 Percentage of participants Interval 12.2 to 21.2	11.2 Percentage of participants Interval 7.3 to 15.1

SECONDARY outcome

Timeframe: Baseline to EOT (up to week 104)

Population: The analysis population was the FAS.

Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Participants Who Received Rescue Therapy (Composite of RBC Transfusions (All Participants) and Darbepoetin Alfa Use (Roxadustat Treated Participants Only)	46 Participants	28 Participants

SECONDARY outcome

Timeframe: Weeks 37 to 52 and 53 to 104

Population: The analysis population was the FAS.

Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Mean Monthly Intravenous Iron Per Participant During Weeks 37 to 52 and 53 to 104 Weeks 37 to 52	11.028 mg per month Standard Deviation 64.282	13.208 mg per month Standard Deviation 46.408
Mean Monthly Intravenous Iron Per Participant During Weeks 37 to 52 and 53 to 104 Weeks 53 to 104	18.702 mg per month Standard Deviation 68.074	31.315 mg per month Standard Deviation 95.306

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to First Use of IV Iron Supplementation Year 0.5	4.3 Percentage of participants Interval 2.0 to 6.5	11.8 Percentage of participants Interval 8.0 to 15.6
Time to First Use of IV Iron Supplementation Year 1	10 Percentage of participants Interval 6.5 to 13.5	19.2 Percentage of participants Interval 14.5 to 23.9
Time to First Use of IV Iron Supplementation Year 1.5	15.9 Percentage of participants Interval 11.5 to 20.2	24.2 Percentage of participants Interval 19.0 to 29.4
Time to First Use of IV Iron Supplementation Year 2	24.9 Percentage of participants Interval 18.8 to 31.0	29.1 Percentage of participants Interval 23.1 to 35.1

SECONDARY outcome

Timeframe: Day 1 to week 36, weeks 37 to 52, weeks 53 to 104, efficacy emergent period (up to week 104)

Population: The analysis population was the FAS.

Percentage of participants with oral iron use only were calculated based on total number of participants within the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Percentage of Participants With Oral Iron Use Only During efficacy emergent period	50.6 Percentage of Participants	52.7 Percentage of Participants
Percentage of Participants With Oral Iron Use Only During day 1 to week 36	55.3 Percentage of Participants	55.1 Percentage of Participants
Percentage of Participants With Oral Iron Use Only During week 37 to 52	55.6 Percentage of Participants	55.4 Percentage of Participants
Percentage of Participants With Oral Iron Use Only During week 53 to 104	53.1 Percentage of Participants	50.6 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 8, 28, 52, 104

Population: The analysis population was the FAS.

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol Change from BL to week 8	-0.92 mmol/L Standard Deviation 0.98	-0.046 mmol/L Standard Deviation 0.836
Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol Change from BL to week 28	-0.531 mmol/L Standard Deviation 1.153	0.016 mmol/L Standard Deviation 0.953
Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol Change from BL to week 52	-0.524 mmol/L Standard Deviation 1.232	-0.111 mmol/L Standard Deviation 1.097
Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol Change from BL to week 104	-0.695 mmol/L Standard Deviation 1.284	-0.197 mmol/L Standard Deviation 1.171

SECONDARY outcome

Timeframe: Baseline and weeks 8, 28, 52, 104

Population: The analysis population was the FAS.

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio Change from BL to Week 8	-0.209 Ratio Standard Deviation 0.665	-0.049 Ratio Standard Deviation 0.629
Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio Change from BL to Week 28	0.016 Ratio Standard Deviation 0.893	0.053 Ratio Standard Deviation 0.747
Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio Change from BL to Week 52	0.014 Ratio Standard Deviation 1.095	-0.065 Ratio Standard Deviation 0.871
Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio Change from BL to Week 104	-0.069 Ratio Standard Deviation 1.579	0.012 Ratio Standard Deviation 1.06

SECONDARY outcome

Timeframe: Baseline and weeks 8, 28, 52, 104

Population: The analysis population was the FAS.

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol Change from BL to week 8	-0.729 mmoL/L Standard Deviation 0.9	-0.045 mmoL/L Standard Deviation 0.787
Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol Change from BL to week 28	-0.392 mmoL/L Standard Deviation 1.098	0.02 mmoL/L Standard Deviation 0.911
Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol Change from BL to week 52	-0.383 mmoL/L Standard Deviation 1.19	-0.114 mmoL/L Standard Deviation 1.062
Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol Change from BL to week 104	-0.562 mmoL/L Standard Deviation 1.162	-0.15 mmoL/L Standard Deviation 1.151

SECONDARY outcome

Timeframe: Baseline and weeks 8, 28, 52, 104

Population: The analysis population was the FAS.

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1) Change from BL to week 8	-0.184 Grams per liter (g/L) Standard Deviation 0.222	0.026 Grams per liter (g/L) Standard Deviation 0.204
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1) Change from BL to week 28	-0.104 Grams per liter (g/L) Standard Deviation 0.258	0.055 Grams per liter (g/L) Standard Deviation 0.217
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1) Change from BL to week 52	-0.12 Grams per liter (g/L) Standard Deviation 0.254	0.027 Grams per liter (g/L) Standard Deviation 0.229
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1) Change from BL to week 104	-0.116 Grams per liter (g/L) Standard Deviation 0.311	-0.018 Grams per liter (g/L) Standard Deviation 0.242

SECONDARY outcome

Timeframe: Baseline and weeks 8, 28, 52, 104

Population: The analysis population was the FAS.

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB) Change from BL to week 8	-16.5 Milligrams per deciliter (mg/dL) Standard Deviation 19.581	-0.71 Milligrams per deciliter (mg/dL) Standard Deviation 17.791
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB) Change from BL to week 28	-10.659 Milligrams per deciliter (mg/dL) Standard Deviation 23.644	0.091 Milligrams per deciliter (mg/dL) Standard Deviation 19.672
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB) Change from BL to week 52	-10.74 Milligrams per deciliter (mg/dL) Standard Deviation 25.155	-3.539 Milligrams per deciliter (mg/dL) Standard Deviation 23.811
Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB) Change from BL to week 104	-13.561 Milligrams per deciliter (mg/dL) Standard Deviation 25.461	-2.038 Milligrams per deciliter (mg/dL) Standard Deviation 25.857

SECONDARY outcome

Timeframe: Baseline and weeks 8, 28, 52, 104

Population: The analysis population was the FAS.

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio Change from BL to week 8	-0.031 Ratio Standard Deviation 0.185	-0.019 Ratio Standard Deviation 0.13
Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio Change from BL to week 28	-0.026 Ratio Standard Deviation 0.208	-0.034 Ratio Standard Deviation 0.159
Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio Change from BL to week 52	-0.025 Ratio Standard Deviation 0.254	-0.038 Ratio Standard Deviation 0.191
Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio Change from BL to week 104	-0.044 Ratio Standard Deviation 0.238	-0.009 Ratio Standard Deviation 0.218

SECONDARY outcome

Timeframe: Weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

Missing category for fasting only includes non-fasting participants and the participants with missing values.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 12-28: Yes (Regardless Fasting Status)	147 Participants	111 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 12-28: No (Regardless Fasting Status)	20 Participants	33 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 12-28: Missing (Regardless Fasting Status)	10 Participants	8 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 12-28: Yes (Fasting only)	90 Participants	69 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 12-28: No (Fasting only)	11 Participants	18 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 12-28: Missing (Fasting only)	76 Participants	65 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 36-52: Yes (Regardless Fasting Status)	129 Participants	104 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 36-52: No (Regardless Fasting Status)	26 Participants	31 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 36-52: Missing (Regardless Fasting Status)	22 Participants	17 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 36-52: Yes (Fasting only)	78 Participants	57 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 36-52: No (Fasting only)	15 Participants	22 Participants
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Weeks 36-52: Missing (Fasting only)	84 Participants	73 Participants

SECONDARY outcome

Timeframe: Weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

Achieved antihypertensive treatment goal was defined as SBP < 130 mmHg and DBP < 80 mmHg over an evaluation period defined as the average of available values in weeks 12 to 28 and 36 to 52.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Participants Who Had Achieved Antihypertensive Treatment Goal Weeks 12-28: Yes	76 Participants	64 Participants
Number of Participants Who Had Achieved Antihypertensive Treatment Goal Weeks 12-28: No	228 Participants	212 Participants
Number of Participants Who Had Achieved Antihypertensive Treatment Goal Week 12-28: Missing	18 Participants	16 Participants
Number of Participants Who Had Achieved Antihypertensive Treatment Goal Weeks 36-52: Yes	80 Participants	64 Participants
Number of Participants Who Had Achieved Antihypertensive Treatment Goal Weeks 36-52: No	196 Participants	193 Participants
Number of Participants Who Had Achieved Antihypertensive Treatment Goal Weeks 36-52: Missing	46 Participants	35 Participants

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

Baseline SF-36 PCS was defined as the SF-36 PCS value on day 1.The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The PCS was calculated based on all 8 scales and ranged from 5.02-79.78. For each of these above scales, higher scores always indicated better health status.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in SF-36 Physical Component Score (PCS) Change from BL to weeks 12-28	1.222 Units on a scale Interval 0.54 to 1.904	2.29 Units on a scale Interval 1.576 to 3.004
Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in SF-36 Physical Component Score (PCS) Change from BL to weeks 36-52	1.083 Units on a scale Interval 0.358 to 1.808	1.686 Units on a scale Interval 0.939 to 2.433

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

Baseline FACT-An AnS was defined as the FACT-An AnS value on day 1. Together with the functional assessment of cancer therapy - general (FACT-G), the AnS is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the fatigue score) plus 7 items related to anemia. The Anemia AnS score range is 0 to 80. Higher scores indicated better QoL.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score Change from BL to weeks 12-28	4.71 Units on a scale Interval 3.558 to 5.861	5.238 Units on a scale Interval 4.029 to 6.446
Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score Change from BL to weeks 36-52	3.661 Units on a scale Interval 2.355 to 4.967	4.608 Units on a scale Interval 3.252 to 5.964

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

Baseline FACT-An total score was defined on day 1. Total Fact-An score is composed of FACT-G and Ans scales. FACT-G contains 27 items that cover four dimensions of well-being: physical well being (PWB) - 7 items, functional well being (FWB) - 7 items, social/family well being (SWB) - 7 items, and emotional well being (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score was obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range was 0-188. A higher score indicated better QoL.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Total Score Change from BL to weeks 12-28	7.761 Units on a scale Interval 5.501 to 10.02	8.665 Units on a scale Interval 6.299 to 11.031
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Total Score Change from BL to weeks 36-52	5.492 Units on a scale Interval 2.915 to 8.069	7.259 Units on a scale Interval 4.593 to 9.925

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

Baseline FACT-An total TOI Score was defined on day 1. Total FACT-An TOI score is a sum of PWB subscale score, FWB subscale score and Ans scale score. Fact-An TOI scale contains 14 items that cover four dimensions of well-being: PWB -7 items, FWB -7 items, where score range for each PWB subscale and FWB subscale is 0-28. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia, where score range for Ans scale is 0-80. The total score was obtained by summation of the scores from PWB, FWB and AnS. The FACT-An Total TOI score range was 0-136. A higher score indicated better QoL.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Trial Outcome Index (TOI) Score Change from BL to weeks 12-28	6.798 Units on a scale Standard Deviation 17.830	6.876 Units on a scale Standard Deviation 16.960
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Trial Outcome Index (TOI) Score Change from BL to weeks 36-52	5.602 Units on a scale Standard Deviation 19.302	5.595 Units on a scale Standard Deviation 19.922

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, with participants who had available data.

Baseline assessment was defined as the value on day 1. The EQ-5D-5L is a self-reported questionnaire, used as a measure of respondents' health related quality of life (HRQoL) and utility values. The EQ-5D consists of the descriptive system and the VAS. The EQ-5D descriptive system comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The VAS records the respondent's self rated health status on a graduated (0-100) scale, where the endpoints are labeled 'best imaginable health state' and 'worst imaginable health state' with higher scores for higher HRQoL.

Outcome measures

Measure	Roxadustat n=300 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=271 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score	5.137 Units on a scale Interval 3.498 to 6.776	4.353 Units on a scale Interval 2.643 to 6.064

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS, with participants who had available data.

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Multiply scores by 100 to express in percentages. Percent work time missed due to problem: Q2/(Q2+Q4).

Outcome measures

Measure	Roxadustat n=35 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=49 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed Change from BL to average in weeks 12-28	-3.793 Percent work time Standard Deviation 32.987	0.842 Percent work time Standard Deviation 21
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed Change from BL to average in weeks 36-52	-0.078 Percent work time Standard Deviation 37.047	0.216 Percent work time Standard Deviation 23.483

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS, with participants who had available data.

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent impairment while working due to problem: Q5/10.

Outcome measures

Measure	Roxadustat n=34 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=50 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Impairment While Working Change from BL to weeks 36-52	-7.879 Percent impairment Standard Deviation 25.872	1.083 Percent impairment Standard Deviation 23.102
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Impairment While Working Change from BL to weeks 12-28	-6.618 Percent impairment Standard Deviation 22.419	-2.433 Percent impairment Standard Deviation 28.598

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS, with participants who had available data.

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)].

Outcome measures

Measure	Roxadustat n=32 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=49 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment Change from BL to weeks 12-28	-6.112 Percent impairment Standard Deviation 23.21	-1.217 Percent impairment Standard Deviation 20.743
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment Change From BL to weeks 36-52	2.817 Percent impairment Standard Deviation 30.432	0.197 Percent impairment Standard Deviation 23.431

SECONDARY outcome

Timeframe: Baseline, weeks 12 to 28 and 36 to 52

Population: The analysis population was the FAS.

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent activity impairment due to problem: Q6/10.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Activity Impairment Change from BL to weeks 12-28	-9.581 Percent impairment Standard Deviation 27.367	-9.34 Percent impairment Standard Deviation 27.09
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Activity Impairment Change from BL to weeks 36-52	-9.365 Percent impairment Standard Deviation 28.956	-8.17 Percent impairment Standard Deviation 27.486

SECONDARY outcome

Timeframe: Weeks 8, 12, 28, 52, 76, 104, last assessment (week 108)

Population: The analysis population was the FAS.

The PGIC is a patient-rated instrument that measured change in participant's overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), when compared to the start of treatment. The percentage of participants presented included very much improved, much improved and minimally improved.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Week 8	76.1 Percentage of Participants	79.4 Percentage of Participants
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Week 12	83.7 Percentage of Participants	83.6 Percentage of Participants
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Week 28	83 Percentage of Participants	81 Percentage of Participants
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Week 52	79.3 Percentage of Participants	79.8 Percentage of Participants
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Week 76	73 Percentage of Participants	74.9 Percentage of Participants
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Week 104	71.8 Percentage of Participants	76 Percentage of Participants
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Last Assessment	70.6 Percentage of Participants	71.4 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and end of study (EOS) (up to 108 weeks)

Population: The analysis population was the FAS.

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 12	-205.722 Picomoles per liter (pmol/L) Standard Deviation 271.752	-201.587 Picomoles per liter (pmol/L) Standard Deviation 346.59
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 20	-99.86 Picomoles per liter (pmol/L) Standard Deviation 334.486	-140.26 Picomoles per liter (pmol/L) Standard Deviation 338.512
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 28	-97.622 Picomoles per liter (pmol/L) Standard Deviation 366.153	-121.574 Picomoles per liter (pmol/L) Standard Deviation 348.136
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 36	-131.801 Picomoles per liter (pmol/L) Standard Deviation 355.463	-120.424 Picomoles per liter (pmol/L) Standard Deviation 362.08
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 44	-120.864 Picomoles per liter (pmol/L) Standard Deviation 368.902	-60.149 Picomoles per liter (pmol/L) Standard Deviation 425.455
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 52	-93.074 Picomoles per liter (pmol/L) Standard Deviation 521.433	-72.383 Picomoles per liter (pmol/L) Standard Deviation 459.342
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 60	-141.264 Picomoles per liter (pmol/L) Standard Deviation 355.419	-47.714 Picomoles per liter (pmol/L) Standard Deviation 459.319
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 68	-110.907 Picomoles per liter (pmol/L) Standard Deviation 422.28	-14.283 Picomoles per liter (pmol/L) Standard Deviation 464.714
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 4	-190.762 Picomoles per liter (pmol/L) Standard Deviation 241.695	-159.174 Picomoles per liter (pmol/L) Standard Deviation 218.981
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 8	-229.471 Picomoles per liter (pmol/L) Standard Deviation 255.677	-208.356 Picomoles per liter (pmol/L) Standard Deviation 309.893
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 76	-99.697 Picomoles per liter (pmol/L) Standard Deviation 412.982	3.424 Picomoles per liter (pmol/L) Standard Deviation 615.735
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 84	-126.615 Picomoles per liter (pmol/L) Standard Deviation 403.693	-1.351 Picomoles per liter (pmol/L) Standard Deviation 576.437
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 92	-98.025 Picomoles per liter (pmol/L) Standard Deviation 460.364	-26.73 Picomoles per liter (pmol/L) Standard Deviation 547.371
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 100	-95.513 Picomoles per liter (pmol/L) Standard Deviation 486.758	31.391 Picomoles per liter (pmol/L) Standard Deviation 750.432
Change From Baseline to Each Scheduled Measurement in Serum Ferritin Week 104	-89.276 Picomoles per liter (pmol/L) Standard Deviation 476.167	26.454 Picomoles per liter (pmol/L) Standard Deviation 730.126
Change From Baseline to Each Scheduled Measurement in Serum Ferritin EOS	78.577 Picomoles per liter (pmol/L) Standard Deviation 680.524	119.157 Picomoles per liter (pmol/L) Standard Deviation 697.39

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and EOS (up to 108 weeks)

Population: The analysis population was the FAS.

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 4	-6 Percentage of saturation Standard Deviation 10.7	-2.1 Percentage of saturation Standard Deviation 11.5
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 8	-5.9 Percentage of saturation Standard Deviation 11.5	-2.4 Percentage of saturation Standard Deviation 10.6
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 12	-2.4 Percentage of saturation Standard Deviation 13.2	-0.5 Percentage of saturation Standard Deviation 12.3
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 20	1.6 Percentage of saturation Standard Deviation 13.9	2.9 Percentage of saturation Standard Deviation 11.6
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 28	1.1 Percentage of saturation Standard Deviation 12.5	4 Percentage of saturation Standard Deviation 12.5
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 36	1.6 Percentage of saturation Standard Deviation 12	3.9 Percentage of saturation Standard Deviation 11.5
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 44	0.6 Percentage of saturation Standard Deviation 12	4.9 Percentage of saturation Standard Deviation 12.9
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 52	1.3 Percentage of saturation Standard Deviation 11.8	5.2 Percentage of saturation Standard Deviation 13.2
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 60	0.4 Percentage of saturation Standard Deviation 12.4	4.8 Percentage of saturation Standard Deviation 12.7
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 68	1 Percentage of saturation Standard Deviation 13.4	6.3 Percentage of saturation Standard Deviation 13.1
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 76	0.1 Percentage of saturation Standard Deviation 12.2	6 Percentage of saturation Standard Deviation 13.7
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 84	1.1 Percentage of saturation Standard Deviation 12.5	6.5 Percentage of saturation Standard Deviation 13.9
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 92	-0.2 Percentage of saturation Standard Deviation 11.7	5.6 Percentage of saturation Standard Deviation 13.8
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 100	0.6 Percentage of saturation Standard Deviation 12.4	5.8 Percentage of saturation Standard Deviation 14
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) Week 104	0.5 Percentage of saturation Standard Deviation 11.9	5 Percentage of saturation Standard Deviation 13.3
Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT) EOS	5.3 Percentage of saturation Standard Deviation 12.3	4.7 Percentage of saturation Standard Deviation 13.9

SECONDARY outcome

Timeframe: Baseline and weeks 12, 28, 36, 44, 60, 84, 104 and EOS (up to 108 weeks)

Population: The analysis population was the FAS.

Percentage of change from baseline to each study visit were calculated for HbA1c. Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 12	0.0021 Percentage of HbA1c Standard Deviation 0.0071	0.001 Percentage of HbA1c Standard Deviation 0.0073
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 28	0.0009 Percentage of HbA1c Standard Deviation 0.0072	0.0015 Percentage of HbA1c Standard Deviation 0.0067
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 36	0.0021 Percentage of HbA1c Standard Deviation 0.0075	0.0021 Percentage of HbA1c Standard Deviation 0.0073
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 44	0.0026 Percentage of HbA1c Standard Deviation 0.0077	0.002 Percentage of HbA1c Standard Deviation 0.0066
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 60	0.0025 Percentage of HbA1c Standard Deviation 0.0083	0.0019 Percentage of HbA1c Standard Deviation 0.0074
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 84	0.0024 Percentage of HbA1c Standard Deviation 0.0093	0.0025 Percentage of HbA1c Standard Deviation 0.0077
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) Week 104	0.0018 Percentage of HbA1c Standard Deviation 0.0086	0.002 Percentage of HbA1c Standard Deviation 0.008
Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c) EOS	0.0031 Percentage of HbA1c Standard Deviation 0.0087	0.0034 Percentage of HbA1c Standard Deviation 0.0081

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)

Population: The analysis population was the FAS.

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 100	2.7 mg/dL Standard Deviation 45.3	4 mg/dL Standard Deviation 48.9
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 4	7 mg/dL Standard Deviation 62.8	10.3 mg/dL Standard Deviation 76.9
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 8	4.1 mg/dL Standard Deviation 60.1	1.3 mg/dL Standard Deviation 40.3
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 12	9.3 mg/dL Standard Deviation 64.5	7.1 mg/dL Standard Deviation 58.2
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 20	6.9 mg/dL Standard Deviation 69.4	4.3 mg/dL Standard Deviation 57.9
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 28	8.7 mg/dL Standard Deviation 66.9	2.8 mg/dL Standard Deviation 37.7
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 36	6.4 mg/dL Standard Deviation 52.5	3.6 mg/dL Standard Deviation 45.3
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 44	3.3 mg/dL Standard Deviation 44.7	0.4 mg/dL Standard Deviation 45.1
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 52	7.1 mg/dL Standard Deviation 69.7	1.1 mg/dL Standard Deviation 41.1
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 60	6.6 mg/dL Standard Deviation 65.6	6.3 mg/dL Standard Deviation 43.1
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 68	3.8 mg/dL Standard Deviation 66.1	5.5 mg/dL Standard Deviation 48.2
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 76	0.9 mg/dL Standard Deviation 41.9	5.8 mg/dL Standard Deviation 55.2
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 84	1.4 mg/dL Standard Deviation 49.1	12 mg/dL Standard Deviation 57.4
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 92	6 mg/dL Standard Deviation 69.5	2.1 mg/dL Standard Deviation 46.5
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 104	-2.6 mg/dL Standard Deviation 60.7	1 mg/dL Standard Deviation 48.6
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose Week 106	-2.4 mg/dL Standard Deviation 31.2	9.2 mg/dL Standard Deviation 53.3
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose EOS	2.5 mg/dL Standard Deviation 58.2	9.8 mg/dL Standard Deviation 43.6

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)

Population: The analysis population was the FAS.

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 4	1.01 Geometric mean ratio Interval 0.99 to 1.03	0.97 Geometric mean ratio Interval 0.95 to 0.99
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 8	1.01 Geometric mean ratio Interval 0.98 to 1.03	0.96 Geometric mean ratio Interval 0.94 to 0.99
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 12	1.02 Geometric mean ratio Interval 1.0 to 1.05	0.95 Geometric mean ratio Interval 0.93 to 0.98
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 20	0.98 Geometric mean ratio Interval 0.95 to 1.01	0.93 Geometric mean ratio Interval 0.9 to 0.96
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 28	0.93 Geometric mean ratio Interval 0.89 to 0.96	0.89 Geometric mean ratio Interval 0.86 to 0.93
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 36	0.93 Geometric mean ratio Interval 0.89 to 0.97	0.89 Geometric mean ratio Interval 0.85 to 0.93
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 44	0.90 Geometric mean ratio Interval 0.86 to 0.93	0.89 Geometric mean ratio Interval 0.84 to 0.93
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 52	0.90 Geometric mean ratio Interval 0.86 to 0.94	0.88 Geometric mean ratio Interval 0.83 to 0.92
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 60	0.90 Geometric mean ratio Interval 0.86 to 0.94	0.86 Geometric mean ratio Interval 0.82 to 0.91
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 68	0.87 Geometric mean ratio Interval 0.83 to 0.91	0.84 Geometric mean ratio Interval 0.79 to 0.89
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 76	0.83 Geometric mean ratio Interval 0.78 to 0.88	0.84 Geometric mean ratio Interval 0.78 to 0.9
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 84	0.83 Geometric mean ratio Interval 0.78 to 0.88	0.83 Geometric mean ratio Interval 0.77 to 0.89
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 92	0.84 Geometric mean ratio Interval 0.79 to 0.9	0.85 Geometric mean ratio Interval 0.79 to 0.9
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 100	0.84 Geometric mean ratio Interval 0.78 to 0.89	0.86 Geometric mean ratio Interval 0.81 to 0.92
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 104	0.84 Geometric mean ratio Interval 0.79 to 0.9	0.84 Geometric mean ratio Interval 0.79 to 0.91
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) Week 106	0.84 Geometric mean ratio Interval 0.78 to 0.9	0.86 Geometric mean ratio Interval 0.79 to 0.92
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR) EOS	0.86 Geometric mean ratio Interval 0.81 to 0.91	0.85 Geometric mean ratio Interval 0.79 to 0.92

SECONDARY outcome

Timeframe: Baseline up to EOS (up to week 108)

Population: The analysis population was the FAS.

Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values (one baseline and all post-treatment values up to EOT period or start of dialysis adjusted on baseline Hb, region, CV history at baseline and the interaction terms (baseline eGFR by timepoint and baseline Hb by timepoint). All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. Baseline assessment was the assessment from day 1 visit. If this value was missing, the value from screening visit was used.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time	-2.95 ml/min per 1.73 m^2 Interval -3.56 to -2.34	-2.89 ml/min per 1.73 m^2 Interval -3.51 to -2.27

SECONDARY outcome

Timeframe: Baseline and weeks 12, 24, 36, 52, 64, 76, 88 and 104

Population: The analysis population was the FAS.

Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 12	1.19 Geometric mean ratio Interval 1.07 to 1.34	1.23 Geometric mean ratio Interval 1.1 to 1.38
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 24	1.18 Geometric mean ratio Interval 1.06 to 1.33	1.22 Geometric mean ratio Interval 1.08 to 1.39
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 36	1.22 Geometric mean ratio Interval 1.07 to 1.4	1.18 Geometric mean ratio Interval 1.03 to 1.36
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 52	1.28 Geometric mean ratio Interval 1.1 to 1.49	1.1 Geometric mean ratio Interval 0.92 to 1.32
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 64	1.23 Geometric mean ratio Interval 1.03 to 1.46	1.11 Geometric mean ratio Interval 0.9 to 1.38
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 76	1.39 Geometric mean ratio Interval 1.14 to 1.7	1.18 Geometric mean ratio Interval 0.94 to 1.48
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 88	1.21 Geometric mean ratio Interval 0.97 to 1.5	1.1 Geometric mean ratio Interval 0.86 to 1.39
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR) Week 104	1.46 Geometric mean ratio Interval 1.17 to 1.82	1.18 Geometric mean ratio Interval 0.92 to 1.51

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

For participants who had doubled their serum creatinine or had chronic dialysis or renal transplant more than once, only their first occurrence during safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Year 0.5	12.9 Percentage of Participants Interval 9.1 to 16.6	8.6 Percentage of Participants Interval 5.3 to 11.9
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Year 1	27.4 Percentage of Participants Interval 22.3 to 32.6	27.2 Percentage of Participants Interval 21.9 to 32.6
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Year 1.5	38.2 Percentage of Participants Interval 32.5 to 44.0	38.8 Percentage of Participants Interval 32.9 to 44.7
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Year 2	46.5 Percentage of Participants Interval 40.5 to 52.5	45.4 Percentage of Participants Interval 39.2 to 51.5

SECONDARY outcome

Timeframe: Baseline up to EOS (up to week 108)

Population: The analysis population was the FAS.

Occurrence of end stage renal disease during the study (i.e from day 1 up to the end of study) was defined as at least one of the following: underwent >30 days dialysis therapy, received kidney transplant, planned kidney transplant, physician recommended renal replacement therapy and participant refused therapy, began dialysis and died < 30 days later.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Participants With End Stage Renal Disease (ESRD)	110 Participants	107 Participants

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

Chronic kidney disease progression was defined as date of occurrence of chronic dialysis or date of renal transplant or doubled serum creatinine or date of death, whichever came first. For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Year 0.5	14 Percentage of participants Interval 10.1 to 17.9	10.2 Percentage of participants Interval 6.7 to 13.8
Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Year 1	30.9 Percentage of participants Interval 25.6 to 36.2	29.5 Percentage of participants Interval 24.1 to 34.9
Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Year 1.5	42.1 Percentage of participants Interval 36.4 to 47.8	42.6 Percentage of participants Interval 36.6 to 48.5
Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Year 2	49.9 Percentage of participants Interval 44.0 to 55.8	51 Percentage of participants Interval 44.9 to 57.0

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to Chronic Dialysis or Renal Transplant or Death Year 0.5	12.7 Percentage of participants Interval 9.0 to 16.4	9.2 Percentage of participants Interval 5.8 to 12.6
Time to Chronic Dialysis or Renal Transplant or Death Year 1	27.1 Percentage of participants Interval 22.0 to 32.2	26.2 Percentage of participants Interval 21.0 to 31.4
Time to Chronic Dialysis or Renal Transplant or Death Year 1.5	37.1 Percentage of participants Interval 31.6 to 42.7	37.7 Percentage of participants Interval 31.9 to 43.5
Time to Chronic Dialysis or Renal Transplant or Death Year 2	42.9 Percentage of participants Interval 37.1 to 48.7	45.6 Percentage of participants Interval 39.6 to 51.7

SECONDARY outcome

Timeframe: Year 0.5, 1, 1.5 and 2

Population: The analysis population was the FAS.

For participants who had at least 40% decrease in eGFR from baseline, chronic dialysis or renal transplant during the safety emergent period, only their first occurrence was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by kaplan-meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.

Outcome measures

Measure	Roxadustat n=322 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=292 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Year 0.5	15.4 Percentage of participants Interval 11.3 to 19.5	13 Percentage of participants Interval 9.0 to 16.9
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Year 1	34.5 Percentage of participants Interval 29.0 to 40.0	35.5 Percentage of participants Interval 29.8 to 41.3
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Year 1.5	47.2 Percentage of participants Interval 41.3 to 53.1	50.2 Percentage of participants Interval 44.1 to 56.3
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Year 2	55.7 Percentage of participants Interval 49.7 to 61.7	59.3 Percentage of participants Interval 53.2 to 65.3

SECONDARY outcome

Timeframe: From first dose of study drug up to end of study (up to week 108)

Population: The analysis population was the safety analysis set included all randomized participants who received at least one dose of study drug.

An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. All AEs collected during the safety emergent period were counted as TEAE. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE. All reported deaths after the first study drug administration and up to 28 days after the analysis date of last dose were based on last dosing frequency.

Outcome measures

Measure	Roxadustat n=323 Participants Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=293 Participants Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 mcg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 mcg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of \>= 11.0 g/dL and Hb increase from baseline of \>= 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE	296 Participants	271 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Drug-Related TEAE	78 Participants	66 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Serious TEAE	209 Participants	181 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Drug-Related Serious TEAE	18 Participants	9 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE Leading to Death	34 Participants	34 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Drug-Related TEAE Leading to Death	2 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE Leading to Withdrawal of Treatment	25 Participants	11 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Drug-Related TEAE Leading to Withdraw of Treatment	7 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE NCI CTC Grades 3 or Higher	181 Participants	164 Participants

Adverse Events

Roxadustat

Serious events: 209 serious events

Other events: 223 other events

Deaths: 40 deaths

Darbepoetin Alfa

Serious events: 181 serious events

Other events: 203 other events

Deaths: 37 deaths

Serious adverse events

Measure	Roxadustat n=323 participants at risk Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=293 participants at risk Participants received initial dose of darbepoetin alfa based upon the weight \[either 0.45 μg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks\] as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Blood and lymphatic system disorders Anaemia	1.5% 5/323 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.0% 6/293 • Number of events 7 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Blood and lymphatic system disorders Haemorrhagic anaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Blood and lymphatic system disorders Hypocoagulable state	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Blood and lymphatic system disorders Immune thrombocytopenic purpura	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Blood and lymphatic system disorders Iron deficiency anaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Blood and lymphatic system disorders Thrombocytopenia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Acute coronary syndrome	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Acute myocardial infarction	1.5% 5/323 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.7% 8/293 • Number of events 10 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Angina pectoris	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.7% 5/293 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Atrial fibrillation	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Atrial flutter	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Atrioventricular block complete	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Atrioventricular block second degree	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Bradycardia	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Cardiac arrest	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Cardiac failure	3.7% 12/323 • Number of events 15 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	3.4% 10/293 • Number of events 15 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Cardiac failure acute	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.0% 6/293 • Number of events 7 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Cardiac failure chronic	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Cardiac failure congestive	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	3.4% 10/293 • Number of events 12 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Cardiogenic shock	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Coronary artery disease	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Left ventricular failure	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Long QT syndrome	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Mitral valve incompetence	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Myocardial fibrosis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Myocardial infarction	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Myocardial ischaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Nodal arrhythmia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Pericardial effusion	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Pericarditis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Sinus node dysfunction	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Supraventricular tachycardia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Trifascicular block	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Cardiac disorders Ventricular tachycardia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Congenital, familial and genetic disorders Congenital cystic kidney disease	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Congenital, familial and genetic disorders Lown-Ganong-Levine syndrome	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Congenital, familial and genetic disorders Spinocerebellar ataxia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Ear and labyrinth disorders Deafness neurosensory	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Endocrine disorders Thyroid mass	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Eye disorders Glaucoma	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Eye disorders Macular degeneration	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Eye disorders Retinal artery occlusion	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Abdominal incarcerated hernia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Abdominal pain	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Abdominal pain upper	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Anal haemorrhage	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Ascites	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Bloody peritoneal effluent	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Colitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Colitis microscopic	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Constipation	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Diarrhoea	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Diverticulum intestinal	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Duodenal ulcer	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Dysphagia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Enteritis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Enterocolitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Food poisoning	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastric antral vascular ectasia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastric haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastric ulcer	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastric ulcer perforation	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastritis	0.62% 2/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastritis erosive	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastritis haemorrhagic	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Haematemesis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Haematochezia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Intestinal ischaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Large intestine perforation	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Melaena	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Nausea	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Oedematous pancreatitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Pancreatitis	0.31% 1/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Pancreatitis acute	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Reactive gastropathy	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Subileus	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Tongue haemorrhage	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Vomiting	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Asthenia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Cardiac death	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Catheter site haemorrhage	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Catheter site pain	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Chest pain	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Complication associated with device	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Death	1.5% 5/323 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.4% 4/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders General physical health deterioration	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.4% 4/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Generalised oedema	0.62% 2/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Inflammation	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Malaise	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Multiple organ dysfunction syndrome	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Non-cardiac chest pain	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Oedema peripheral	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Pyrexia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Sudden death	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Bile duct stone	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Biliary colic	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Cholangitis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Cholecystitis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Cholelithiasis	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Hepatic cirrhosis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Hepatic congestion	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Hepatitis toxic	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Jaundice cholestatic	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Liver injury	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Hepatobiliary disorders Portal vein thrombosis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Immune system disorders Anti-neutrophil cytoplasmic antibody positive vasculitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Immune system disorders Drug hypersensitivity	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Immune system disorders Hypersensitivity	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Immune system disorders Renal transplant failure	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Immune system disorders Sarcoidosis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Abscess limb	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Acute hepatitis B	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Bacterial infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Bacterial pyelonephritis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Bronchitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Bronchitis viral	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Catheter site infection	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Cellulitis	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Clostridium colitis	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Clostridium difficile colitis	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Cystitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Device related infection	0.93% 3/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.4% 4/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Device related sepsis	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Diverticulitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Enterococcal sepsis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Enterocolitis bacterial	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Erysipelas	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Escherichia pyelonephritis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Escherichia sepsis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Escherichia urinary tract infection	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Gangrene	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Gastritis viral	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Gastroenteritis	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Gastroenteritis viral	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Groin abscess	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Hepatic cyst infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Hepatitis B	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Herpes zoster	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Influenza	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.4% 4/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Klebsiella sepsis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Localised infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Lower respiratory tract infection	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Lymphangitis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Nosocomial infection	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Oesophageal candidiasis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Orchitis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Osteomyelitis	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Parotitis	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Peritonitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Peritonitis bacterial	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Pneumonia	6.5% 21/323 • Number of events 23 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	4.8% 14/293 • Number of events 17 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Pneumonia bacterial	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Pneumonia viral	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Post procedural sepsis	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Postoperative wound infection	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Pulmonary sepsis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Pyelonephritis acute	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.4% 7/293 • Number of events 10 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Pyelonephritis chronic	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Renal cyst infection	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Respiratory tract infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Salpingo-oophoritis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Sepsis	2.2% 7/323 • Number of events 8 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	3.1% 9/293 • Number of events 9 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Skin infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Soft tissue infection	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Staphylococcal bacteraemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Staphylococcal sepsis	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Staphylococcal skin infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Streptococcal endocarditis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Tubo-ovarian abscess	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Upper respiratory tract infection bacterial	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Urinary tract infection	2.2% 7/323 • Number of events 7 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Urinary tract infection bacterial	1.5% 5/323 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Urinary tract infection enterococcal	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Urinary tract infection pseudomonal	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Urosepsis	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Viral infection	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Arterial bypass occlusion	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Arteriovenous fistula site haematoma	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Arteriovenous fistula thrombosis	2.8% 9/323 • Number of events 9 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.7% 5/293 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Brain contusion	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Chest injury	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Complications of transplanted kidney	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Facial bones fracture	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Fall	0.93% 3/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Femur fracture	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Limb injury	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Multiple injuries	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Peritoneal dialysis complication	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Postoperative wound complication	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Rib fracture	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Shunt malfunction	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Shunt occlusion	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Skin injury	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Splenic rupture	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Synovial rupture	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Tendon rupture	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Tibia fracture	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Toxicity to various agents	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Traumatic intracranial haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Urinary anastomotic leak	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Vascular access malfunction	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Vascular access site bruising	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Vascular access site swelling	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Vascular access site thrombosis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Injury, poisoning and procedural complications Vascular pseudoaneurysm	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Blood glucose increased	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Blood potassium increased	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Blood sodium increased	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations C-reactive protein increased	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Glomerular filtration rate decreased	8.0% 26/323 • Number of events 28 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	8.5% 25/293 • Number of events 37 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Haemoglobin decreased	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Lipase increased	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Occult blood positive	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Alkalosis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Alkalosis hypochloraemic	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Dehydration	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.4% 7/293 • Number of events 10 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Diabetes mellitus	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Diabetic metabolic decompensation	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Fluid overload	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypercalcaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hyperkalaemia	2.2% 7/323 • Number of events 7 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.0% 6/293 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypervolaemia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypocalcaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypochloraemia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypoglycaemia	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hyponatraemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Iron deficiency	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Metabolic acidosis	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Mineral deficiency	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Bone pain	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Gouty arthritis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Pain in extremity	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma gastric	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign neoplasm of thyroid gland	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign renal neoplasm	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer stage I	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Carcinoma in situ of skin	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic myelomonocytic leukaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatocellular carcinoma	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Meningioma	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastasis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal adenocarcinoma	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Parathyroid tumour benign	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer metastatic	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine neoplasm	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Carotid artery stenosis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Central nervous system lesion	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Cerebral infarction	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Cerebral ischaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Cerebrovascular accident	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Cognitive disorder	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Coma	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Diabetic neuropathy	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Dizziness	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Encephalopathy	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Epilepsy	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Haemorrhagic stroke	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Headache	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Hypoglycaemic coma	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Hypoglycaemic unconsciousness	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Hypoxic-ischaemic encephalopathy	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Ischaemic stroke	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Lumbar radiculopathy	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Neuropathy peripheral	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Partial seizures	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Presyncope	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Simple partial seizures	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Somnolence	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Syncope	1.9% 6/323 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Thalamus haemorrhage	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Transient ischaemic attack	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Uraemic encephalopathy	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Product Issues Device dislocation	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Product Issues Device leakage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Psychiatric disorders Alcoholism	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Psychiatric disorders Confusional state	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Psychiatric disorders Delirium	0.93% 3/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Psychiatric disorders Depression	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Psychiatric disorders Frustration tolerance decreased	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Acute kidney injury	2.2% 7/323 • Number of events 8 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.4% 7/293 • Number of events 10 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Acute prerenal failure	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Anuria	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Azotaemia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Chronic kidney disease	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders End stage renal disease	33.4% 108/323 • Number of events 108 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	36.2% 106/293 • Number of events 106 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Haematuria	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Nephropathy toxic	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Obstructive uropathy	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Renal artery stenosis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Renal colic	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Renal cyst haemorrhage	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Renal cyst ruptured	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Renal failure	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Ureterolithiasis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Renal and urinary disorders Urinary bladder rupture	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Reproductive system and breast disorders Menometrorrhagia	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Reproductive system and breast disorders Ovarian cyst	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary disease	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.9% 6/323 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Emphysema	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Hydrothorax	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.62% 2/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.4% 4/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.0% 3/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Pulmonary vasculitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Angioedema	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Decubitus ulcer	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Diabetic foot	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Panniculitis	0.62% 2/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Skin ulcer	0.93% 3/323 • Number of events 3 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Toxic epidermal necrolysis	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Aortic aneurysm	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Aortic intramural haematoma	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Blood pressure fluctuation	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Circulatory collapse	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Deep vein thrombosis	1.2% 4/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Embolism arterial	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Extremity necrosis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Haemorrhage	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Hypertension	2.5% 8/323 • Number of events 11 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.7% 5/293 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Hypertensive crisis	1.5% 5/323 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.7% 5/293 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Hypertensive emergency	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Hypotension	1.2% 4/323 • Number of events 5 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Hypovolaemic shock	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Iliac artery occlusion	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Orthostatic hypotension	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Peripheral arterial occlusive disease	0.93% 3/323 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	1.4% 4/293 • Number of events 4 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Peripheral artery occlusion	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Peripheral artery stenosis	0.31% 1/323 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Peripheral ischaemia	1.2% 4/323 • Number of events 6 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.68% 2/293 • Number of events 2 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Phlebitis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Shock haemorrhagic	0.00% 0/323 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Thrombosis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Venous thrombosis	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.34% 1/293 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Venous thrombosis limb	0.31% 1/323 • Number of events 1 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	0.00% 0/293 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.

Other adverse events

Measure	Roxadustat n=323 participants at risk Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.	Darbepoetin Alfa n=293 participants at risk Participants received initial dose of darbepoetin alfa based upon the weight \[either 0.45 μg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks\] as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
Cardiac disorders Atrial fibrillation	5.0% 16/323 • Number of events 18 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	3.8% 11/293 • Number of events 15 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Constipation	6.5% 21/323 • Number of events 23 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	5.1% 15/293 • Number of events 18 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Diarrhoea	8.4% 27/323 • Number of events 38 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	9.6% 28/293 • Number of events 36 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Nausea	10.8% 35/323 • Number of events 40 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	8.2% 24/293 • Number of events 26 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Gastrointestinal disorders Vomiting	6.5% 21/323 • Number of events 31 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	6.5% 19/293 • Number of events 22 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
General disorders Oedema peripheral	14.9% 48/323 • Number of events 59 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	12.3% 36/293 • Number of events 52 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Bronchitis	6.5% 21/323 • Number of events 27 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	5.8% 17/293 • Number of events 21 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Urinary tract infection	5.3% 17/323 • Number of events 24 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	8.2% 24/293 • Number of events 29 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Infections and infestations Viral upper respiratory tract infection	9.0% 29/323 • Number of events 33 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	8.5% 25/293 • Number of events 30 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Investigations Glomerular filtration rate decreased	10.2% 33/323 • Number of events 35 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	9.6% 28/293 • Number of events 30 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hyperkalaemia	10.5% 34/323 • Number of events 38 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	13.3% 39/293 • Number of events 44 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Hyperphosphataemia	8.7% 28/323 • Number of events 29 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	5.1% 15/293 • Number of events 18 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Metabolism and nutrition disorders Iron deficiency	6.2% 20/323 • Number of events 24 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	8.2% 24/293 • Number of events 33 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Arthralgia	5.6% 18/323 • Number of events 21 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	4.8% 14/293 • Number of events 19 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Back pain	6.2% 20/323 • Number of events 22 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	5.5% 16/293 • Number of events 19 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Musculoskeletal and connective tissue disorders Muscle spasms	7.7% 25/323 • Number of events 33 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	5.1% 15/293 • Number of events 20 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Dizziness	5.0% 16/323 • Number of events 20 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	4.4% 13/293 • Number of events 15 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Nervous system disorders Headache	6.2% 20/323 • Number of events 23 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	4.1% 12/293 • Number of events 12 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Psychiatric disorders Insomnia	5.9% 19/323 • Number of events 19 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	2.7% 8/293 • Number of events 9 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.9% 19/323 • Number of events 20 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	4.1% 12/293 • Number of events 13 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Skin and subcutaneous tissue disorders Pruritus	6.2% 20/323 • Number of events 27 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	4.4% 13/293 • Number of events 13 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
Vascular disorders Hypertension	28.8% 93/323 • Number of events 129 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.	33.1% 97/293 • Number of events 149 • From first dose of study drug up to end of study (up to week 108) Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.

Additional Information

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