Trial Outcomes & Findings for Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (NCT NCT01887600)

NCT ID: NCT01887600

Last Updated: 2024-11-14

Results Overview

Hemoglobin (Hb) response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for participants with baseline Hb \> 8.0 g/dL; or Hb increase 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, erythropoiesis-stimulating agent (ESA), or intravenous (IV) iron prior to Hb response. This was the primary efficacy endpoint for EU (EMA).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 594 participants
• Primary outcome timeframe: Baseline to week 24
• Results posted on: 2024-11-14

Participant Flow

Study population consisted of anemic participants with stages 3, 4 or 5 chronic kidney disease (CKD) (Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2) who were not on dialysis. Participants were recruited from 125 study centers located in 22 countries.

A total of 594 participants with CKD were randomized to one of the 2 treatment arms in a 2:1 ratio receiving roxadustat or placebo. Anemia was defined as a mean Hb ≤ 10.0 g/dL upon repeated measurements during the screening period. Participants needed a ferritin ≥30 ng/mL (≥ 67.4 pmol/L) and transferrin saturation (TSAT) ≥ 5%.

Participant milestones

Measure	Roxadustat Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Overall Study STARTED	391	203
Overall Study Treatment Received	391	203
Overall Study COMPLETED	245	89
Overall Study NOT COMPLETED	146	114

Reasons for withdrawal

Measure	Roxadustat Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Overall Study Death	39	16
Overall Study Lack of Efficacy	3	26
Overall Study Lost to Follow-up	5	1
Overall Study Physician Decision	7	8
Overall Study Protocol Deviation	3	0
Overall Study Withdrawal by Subject	58	52
Overall Study Adverse Event	21	9
Overall Study Non-compliance with study drug	3	0
Overall Study Miscellaneous	6	2
Overall Study Progressive Disease	1	0

Baseline Characteristics

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis

Baseline characteristics by cohort

Measure	Roxadustat n=391 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.	Total n=594 Participants Total of all reporting groups
Age, Continuous	60.6 Year STANDARD_DEVIATION 13.5 • n=5 Participants	61.7 Year STANDARD_DEVIATION 13.8 • n=7 Participants	61.0 Year STANDARD_DEVIATION 13.6 • n=5 Participants
Sex: Female, Male Female	222 Participants n=5 Participants	104 Participants n=7 Participants	326 Participants n=5 Participants
Sex: Female, Male Male	169 Participants n=5 Participants	99 Participants n=7 Participants	268 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	9 Participants n=5 Participants	0 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants	3 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) White	335 Participants n=5 Participants	182 Participants n=7 Participants	517 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	37 Participants n=5 Participants	18 Participants n=7 Participants	55 Participants n=5 Participants
History of Diabetes (Type 1 or 2) Yes	146 Participants n=5 Participants	89 Participants n=7 Participants	235 Participants n=5 Participants
History of Diabetes (Type 1 or 2) No	245 Participants n=5 Participants	114 Participants n=7 Participants	359 Participants n=5 Participants
Iron Repletion at Baseline TSAT >= 20% and Ferritin >= 100 ng/mL	204 Participants n=5 Participants	109 Participants n=7 Participants	313 Participants n=5 Participants
Iron Repletion at Baseline TSAT < 20% or Ferritin < 100 ng/mL	187 Participants n=5 Participants	94 Participants n=7 Participants	281 Participants n=5 Participants
Baseline Hemoglobin (Hb) Value	9.08 g/dL STANDARD_DEVIATION 0.76 • n=5 Participants	9.10 g/dL STANDARD_DEVIATION 0.72 • n=7 Participants	9.08 g/dL STANDARD_DEVIATION 0.75 • n=5 Participants
Baseline Estimated Glomerular Filtration Rate (eGFR)	16.5 mL/min/1.73m^2 STANDARD_DEVIATION 10.2 • n=5 Participants	17.2 mL/min/1.73m^2 STANDARD_DEVIATION 11.7 • n=7 Participants	16.7 mL/min/1.73m^2 STANDARD_DEVIATION 10.7 • n=5 Participants
Time From Chronic Kidney Disease (CKD) Diagnosis	5.65 Years STANDARD_DEVIATION 7.02 • n=5 Participants	4.91 Years STANDARD_DEVIATION 5.99 • n=7 Participants	5.40 Years STANDARD_DEVIATION 6.69 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to week 24

Population: The analysis population was the full analysis set (FAS), which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Hemoglobin (Hb) response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb increase 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, erythropoiesis-stimulating agent (ESA), or intravenous (IV) iron prior to Hb response. This was the primary efficacy endpoint for EU (EMA).

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Participants With a Hemoglobin (Hb) Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy Prior to Hb Response	79.2 Percentage of Participants Interval 74.8 to 83.1	9.9 Percentage of Participants Interval 6.1 to 14.8

PRIMARY outcome

Timeframe: Baseline and weeks 28 to 52

Population: The analysis population was All Randomized, and it consisted of all randomized participants with available data at all time points.

The change from baseline to the average Hb values across weeks 28 to 52 without having received rescue therapy. The Hb values from visit windows at weeks 28, 32, 36, 40, 44, 48 and 52 were used for the calculation of the average of weeks 28 to 52. This was the primary efficacy endpoint for US (FDA).

Outcome measures

Measure	Roxadustat n=312 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=146 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy	1.992 g/dL Interval 1.82 to 2.16	0.300 g/dL Interval 0.09 to 0.51

SECONDARY outcome

Timeframe: Baseline and weeks 28 to 36

Population: The analysis population was the full analysis set (FAS), which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The Hb values from visit windows at weeks 28, 32 and 36 were used for the calculation of the average of weeks 28 to 36.

Outcome measures

Measure	Roxadustat n=311 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=139 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period	2.069 g/dL Interval 1.94 to 2.2	0.470 g/dL Interval 0.3 to 0.64

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Analysis was completed on all values collected on day 1 and weeks 12, 20 and 28.

Outcome measures

Measure	Roxadustat n=342 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=185 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28	-0.650 mmol/L Interval -0.76 to -0.54	0.051 mmol/L Interval -0.08 to 0.18

SECONDARY outcome

Timeframe: Baseline to week 104 (End of Treatment [EOT])

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The time to first use of rescue therapy was calculated (in years) as: (First event date - Analysis date of first dose intake + 1) / 365.25. The First event date was defined as Date of first dose of rescue medication during the efficacy emergent period and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or the end of treatment (EOT) visit, whichever occurred first. Data reported was analysed by Kaplan-Meier estimate for cumulative proportion. Medication onset date was the date of the first use of rescue medication.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron) Year 2	26.3 Percentage of participants Interval 20.2 to 32.4	57.8 Percentage of participants Interval 48.7 to 66.9
Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron) Year 0.5	6.1 Percentage of participants Interval 3.6 to 8.7	33.3 Percentage of participants Interval 26.5 to 40.1
Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron) Year 1	13.0 Percentage of participants Interval 9.3 to 16.7	50.1 Percentage of participants Interval 42.4 to 57.7
Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron) Year 1.5	22.0 Percentage of participants Interval 16.6 to 27.3	52.5 Percentage of participants Interval 44.5 to 60.5

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from BL in SF-36 VT sub-score to the average value in weeks 12-28 was calculated using the physical component scores (PCS) of SF-36. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. The survey measures eight dimensions or scales: (1) physical functioning (PF) (10 items); (2) role limitations due to physical health problems (RP) (3 items); (3) bodily pain (BP) (2 items); (4) social functioning (SF) (2 items); (5) general health perceptions (GH) (5 items); (6) role limitations due to emotional problems (RE) (3 items); (7) vitality, energy or fatigue (VT) (4 items); and (8) mental health (MH) (5 items). The SF-36 scores ranged from 0-100 with higher scores indicating better health status.

Outcome measures

Measure	Roxadustat n=340 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=185 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28	2.788 Units on a Scale Interval 1.56 to 4.01	1.661 Units on a Scale Interval 0.23 to 3.1

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline in SF-36 PF normalized sub-score compared to the average PF sub-score of weeks 12 to 28. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Change from baseline in PF sub score of SF-36 to the average of weeks 12-28 was compared by treatment arm for all participants (primary analysis) and in the subsets of participants with baseline PF sub score below 35 and equal or above 35. The SF-36 scores ranged from 0-100 with higher scores indicating better health status. All available SF-36 PF values were used i.e., both scheduled and unscheduled for the calculation of the average PF sub-score of weeks 12 to 28.

Outcome measures

Measure	Roxadustat n=340 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=185 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28	1.344 Units on a Scale Interval 0.15 to 2.54	0.632 Units on a Scale Interval -0.76 to 2.03

SECONDARY outcome

Timeframe: Baseline and weeks 20 to 28

Population: The analysis population was the per protocol set (PPS), which consisted of all FAS participants who did not meet any reasons for exclusion from the PPS and had all available data at all time points.

The MAP was derived for each visit from the average systolic (SBP) and diastolic blood pressure (DBP) calculated for each visit using the three readings and the following equation: MAP = (2/3) * DBP + (1/3) * SBP. Baseline assessment was the assessment on day 1 (average of the three readings). If the baseline assessment was missing, then the latest available value prior to first drug administration was used.

Outcome measures

Measure	Roxadustat n=310 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=146 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28	-0.814 mmHg Interval -1.83 to 0.2	-1.656 mmHg Interval -2.91 to -0.41

SECONDARY outcome

Timeframe: Baseline and year 0.5, year 1, year 1.5 and year 2

Population: The analysis population was the PPS, which consisted of all FAS participants who did not meet any reasons for exclusion from the PPS and had all available data at all time points.

Occurrence of hypertension was defined as SBP increase from BL ≥20 mmHg and SBP >170 mmHg or DBP increase from BL ≥15 mmHg and DBP ≥110 mmHg. Time to first occurrence of hypertension was defined as first date where SBP criterion or DBP criterion is met, whichever occurred first. Data was analysed using Kaplan-Meier estimate for cumulative proportion.

Outcome measures

Measure	Roxadustat n=359 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=183 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Occurrence of Hypertension Year 1	14.8 Percentage of participants Interval 10.9 to 18.8	12.5 Percentage of participants Interval 7.3 to 17.7
Time to First Occurrence of Hypertension Year 0.5	11.4 Percentage of participants Interval 7.9 to 14.8	10.1 Percentage of participants Interval 5.5 to 14.7
Time to First Occurrence of Hypertension Year 1.5	17.5 Percentage of participants Interval 13.0 to 21.9	12.5 Percentage of participants Interval 7.3 to 17.7
Time to First Occurrence of Hypertension Year 2	18.5 Percentage of participants Interval 13.7 to 23.3	12.5 Percentage of participants Interval 7.3 to 17.7

SECONDARY outcome

Timeframe: Baseline to week 108

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

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 chronic dialysis (acute or chronic) are 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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time	-2.65 ml/min per 1.73 m^2 per year Interval -3.29 to -2.02	-3.24 ml/min per 1.73 m^2 per year Interval -4.21 to -2.28

SECONDARY outcome

Timeframe: Weeks 28 to 36

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

All scheduled and unscheduled hemoglobin values from weeks 28 to 36 were taken into account for calculating the average values.

Outcome measures

Measure	Roxadustat n=311 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=139 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period	11.106 g/dL Interval 10.97 to 11.24	9.468 g/dL Interval 9.29 to 9.65

SECONDARY outcome

Timeframe: Weeks 44 to 52

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

All scheduled and unscheduled hemoglobin values from weeks 44 to 52 were taken into account for calculating the average values.

Outcome measures

Measure	Roxadustat n=287 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=118 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period	10.984 g/dL Interval 10.85 to 11.12	9.381 g/dL Interval 9.19 to 9.58

SECONDARY outcome

Timeframe: Weeks 96 to 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

All scheduled and unscheduled hemoglobin values from weeks 96 to 104 were taken into account for calculating the average values.

Outcome measures

Measure	Roxadustat n=120 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=32 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period	10.816 g/dL Interval 10.63 to 11.0	9.324 g/dL Interval 9.01 to 9.64

SECONDARY outcome

Timeframe: Baseline to week 24

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Hb response was measured as Yes or No; Yes was defined as Hb ≥11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL. For a participant without rescue therapy before Hb response (defined in 1 primary outcome), the time to achieve Hb response was calculated (in weeks) as: (First event date - Analysis date of first dose intake + 1) / 7 where First event date was defined as First date of both values that met the criteria for response. Participants who discontinued or received rescue therapy prior to the first Hb response or before the second consecutive Hb value defined as a response were classified as non responders and were censored at week 24 or end of efficacy emergent period, whichever came first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint Week 8	59.8 Percentage of participants Interval 54.7 to 64.9	6.2 Percentage of participants Interval 2.8 to 9.7
Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint Week 16	83.4 Percentage of participants Interval 79.3 to 87.5	9.4 Percentage of participants Interval 5.1 to 13.7
Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint Week 4	26.0 Percentage of participants Interval 21.6 to 30.4	3.5 Percentage of participants Interval 0.9 to 6.0
Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint Week 24	89.1 Percentage of participants Interval 85.5 to 92.6	11.6 Percentage of participants Interval 6.8 to 16.5

SECONDARY outcome

Timeframe: Baseline (day 1) 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, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

All scheduled and unscheduled hemoglobin values that belong to each visit window were taken into account using one value per analysis window. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 1	0.390 g/dL Interval 0.29 to 0.49	-0.006 g/dL Interval -0.12 to 0.11
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 2	0.977 g/dL Interval 0.87 to 1.08	0.039 g/dL Interval -0.09 to 0.17
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 6	1.927 g/dL Interval 1.79 to 2.06	0.100 g/dL Interval -0.07 to 0.27
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 8	2.236 g/dL Interval 2.1 to 2.37	0.178 g/dL Interval 0.01 to 0.35
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 10	2.129 g/dL Interval 1.99 to 2.26	0.180 g/dL Interval 0.01 to 0.35
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 20	2.191 g/dL Interval 2.04 to 2.34	0.367 g/dL Interval 0.18 to 0.56
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 24	1.802 g/dL Interval 1.66 to 1.95	0.355 g/dL Interval 0.16 to 0.55
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 28	1.996 g/dL Interval 1.85 to 2.14	0.435 g/dL Interval 0.24 to 0.63
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 32	1.911 g/dL Interval 1.77 to 2.05	0.324 g/dL Interval 0.13 to 0.52
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 48	1.695 g/dL Interval 1.54 to 1.85	0.249 g/dL Interval 0.03 to 0.46
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 52	1.939 g/dL Interval 1.78 to 2.1	0.298 g/dL Interval 0.07 to 0.52
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 80	1.752 g/dL Interval 1.57 to 1.93	0.308 g/dL Interval 0.01 to 0.61
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 84	1.854 g/dL Interval 1.66 to 2.05	0.480 g/dL Interval 0.14 to 0.82
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 104	1.857 g/dL Interval 1.64 to 2.08	0.511 g/dL Interval 0.11 to 0.91
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 4	1.591 g/dL Interval 1.47 to 1.71	0.119 g/dL Interval -0.04 to 0.27
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 12	2.412 g/dL Interval 2.28 to 2.55	0.322 g/dL Interval 0.15 to 0.49
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 14	2.214 g/dL Interval 2.08 to 2.35	0.163 g/dL Interval 0.0 to 0.33
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 16	2.365 g/dL Interval 2.23 to 2.5	0.378 g/dL Interval 0.2 to 0.56
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 18	2.087 g/dL Interval 1.95 to 2.23	0.246 g/dL Interval 0.06 to 0.43
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 22	1.873 g/dL Interval 1.73 to 2.02	0.222 g/dL Interval 0.03 to 0.41
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 36	2.100 g/dL Interval 1.95 to 2.25	0.410 g/dL Interval 0.21 to 0.61
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 40	1.887 g/dL Interval 1.74 to 2.03	0.241 g/dL Interval 0.04 to 0.45
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 44	1.977 g/dL Interval 1.82 to 2.13	0.278 g/dL Interval 0.06 to 0.49
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 56	1.725 g/dL Interval 1.56 to 1.88	0.085 g/dL Interval -0.16 to 0.33
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 60	1.988 g/dL Interval 1.81 to 2.16	0.354 g/dL Interval 0.09 to 0.62
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 64	1.637 g/dL Interval 1.45 to 1.82	0.233 g/dL Interval -0.06 to 0.52
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 68	1.913 g/dL Interval 1.74 to 2.09	0.414 g/dL Interval 0.13 to 0.7
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 72	1.765 g/dL Interval 1.58 to 1.95	0.328 g/dL Interval 0.03 to 0.63
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 76	1.859 g/dL Interval 1.67 to 2.05	0.674 g/dL Interval 0.36 to 0.99
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 88	1.570 g/dL Interval 1.38 to 1.76	0.399 g/dL Interval 0.06 to 0.74
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 92	1.800 g/dL Interval 1.6 to 2.0	0.418 g/dL Interval 0.06 to 0.78
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 96	1.701 g/dL Interval 1.49 to 1.91	0.139 g/dL Interval -0.23 to 0.51
Hb Change From BL to Each Post-Dosing Time Point Hb Change From BL to Week 100	1.763 g/dL Interval 1.57 to 1.96	0.315 g/dL Interval -0.03 to 0.66

SECONDARY outcome

Timeframe: Baseline and weeks 28 to 36

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The Hb values from visit windows from weeks 28 to 36 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing).

Outcome measures

Measure	Roxadustat n=312 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=146 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy	2.013 g/dL Interval 1.88 to 2.15	0.399 g/dL Interval 0.22 to 0.58

SECONDARY outcome

Timeframe: Baseline and weeks 44 to 52

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The Hb values from visit windows from weeks 44 to 52 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing).

Outcome measures

Measure	Roxadustat n=291 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=123 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy	1.886 g/dL Interval 1.75 to 2.03	0.292 g/dL Interval 0.1 to 0.48

SECONDARY outcome

Timeframe: Baseline and weeks 96 to 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The Hb values from visit windows from weeks 96 to 104 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing).

Outcome measures

Measure	Roxadustat n=124 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=32 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy	1.779 g/dL Interval 1.6 to 1.96	0.327 g/dL Interval 0.01 to 0.64

SECONDARY outcome

Timeframe: Baseline and weeks 28 to 36

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The percentage of Hb values measured during weeks 28-36 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Outcome measures

Measure	Roxadustat n=311 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=139 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy	64.18 Percentage of Hb values Standard Deviation 32.90	34.20 Percentage of Hb values Standard Deviation 39.47

SECONDARY outcome

Timeframe: Baseline and weeks 44 to 52

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The percentage of Hb values measured during weeks 44-52 with values within 10.0 - 12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Outcome measures

Measure	Roxadustat n=287 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=118 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy	69.39 Percentage of Hb values Standard Deviation 32.47	35.45 Percentage of Hb values Standard Deviation 41.75

SECONDARY outcome

Timeframe: Baseline and weeks 96 to 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The percentage of Hb values measured during weeks 96-104 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Outcome measures

Measure	Roxadustat n=120 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=32 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy	64.65 Percentage of Hb values Standard Deviation 37.16	40.63 Percentage of Hb values Standard Deviation 44.39

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Time to first hospitalization was defined in years as the First event date during the Efficacy Emergent Period - (Analysis date of first dose intake +1)/365.25. The first event date was defined as the Date of first admission. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Analysis date of first dose intake was defined as the date of first study drug intake collected on day 1 visit. For participants who experienced more than one hospitalization, only their first event following study treatment was used. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Hospitalization Year 0.5	32.2 Percentage of participants Interval 27.3 to 37.0	39.8 Percentage of participants Interval 32.7 to 46.9
Time to First Hospitalization Year 1.5	62.1 Percentage of participants Interval 56.3 to 67.9	64.0 Percentage of participants Interval 54.5 to 73.4
Time to First Hospitalization Year 1	49.9 Percentage of participants Interval 44.6 to 55.2	49.3 Percentage of participants Interval 41.8 to 56.8
Time to First Hospitalization Year 2	NA Percentage of participants Due to low number of events estimate for this time point could not be calculated.	67.8 Percentage of participants Interval 57.9 to 77.7

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of participants with hospitalizations.

The sum of the durations of all hospitalizations in days was adjusted for the duration of exposure. Derived only for participants with at least one hospitalization. The number of days of hospitalization per PEY was calculated as the sum of the durations of all hospitalizations in days [Minimum (Date of discharge, End of Efficacy Emergent Period) - Date of admission + 1] / [Duration of Efficacy Emergent Period in days / 365.25]. Participants can have more than one hospitalization.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Number of Days of Hospitalization Per Patient Exposure Year (PEY)	14.567 Number of days per PEY Standard Deviation 29.214	15.885 Number of days per PEY Standard Deviation 30.224

SECONDARY outcome

Timeframe: Baseline to week 24

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Time to first use of rescue therapy in years. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Use of Rescue Therapy (Composite of RBC, Transfusions, ESA Use, and IV Iron) in the First 24 Weeks of Treatment Week 6	0.8 Percentage of participants Interval 0.0 to 1.7	6.0 Percentage of participants Interval 2.7 to 9.3
Time to First Use of Rescue Therapy (Composite of RBC, Transfusions, ESA Use, and IV Iron) in the First 24 Weeks of Treatment Week 12	2.5 Percentage of participants Interval 0.9 to 4.1	15.8 Percentage of participants Interval 10.7 to 20.9
Time to First Use of Rescue Therapy (Composite of RBC, Transfusions, ESA Use, and IV Iron) in the First 24 Weeks of Treatment Week 18	3.3 Percentage of participants Interval 1.5 to 5.2	25.3 Percentage of participants Interval 19.2 to 31.5
Time to First Use of Rescue Therapy (Composite of RBC, Transfusions, ESA Use, and IV Iron) in the First 24 Weeks of Treatment Week 24	5.5 Percentage of participants Interval 3.1 to 7.9	32.1 Percentage of participants Interval 25.4 to 38.7

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Time to First Use of RBC Transfusions during efficacy emergent period. For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Use of RBC Transfusions Year 0.5	2.9 Percentage of participants Interval 1.1 to 4.7	15.2 Percentage of participants Interval 10.1 to 20.4
Time to First Use of RBC Transfusions Year 1	5.6 Percentage of participants Interval 3.0 to 8.1	20.2 Percentage of participants Interval 14.2 to 26.2
Time to First Use of RBC Transfusions Year 1.5	12.1 Percentage of participants Interval 7.7 to 16.5	21.8 Percentage of participants Interval 15.1 to 28.5
Time to First Use of RBC Transfusions Year 2	15.0 Percentage of participants Interval 9.9 to 20.1	27.0 Percentage of participants Interval 17.7 to 36.4

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

During efficacy emergent period, the mean monthly number of RBC packs was calculated as the sum of units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. In case of missing number of packs, values were estimated based on 1 unit for packed cells = 250 mL or 1 unit for whole blood = 500 mL. Participants without RBC transfusion were included with a value of zero. No estimation if values were missing.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Mean Monthly Number of RBC Packs	0.041 RBC Packs per 28 days Standard Deviation 0.397	0.089 RBC Packs per 28 days Standard Deviation 0.243

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

During efficacy emergent period, the mean monthly volume of blood transfused was calculated as the sum of blood volume transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. The mean monthly volume transfused was calculated as the sum of the volume transfused between the first dose and up to the last dose in the period divided by duration (in days) and multiplied by 28 days. Participants without RBC transfusion were included with a value of zero.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Mean Monthly Volume of Blood Transfused	11.331 Milliliters (ml) per 28 days Standard Deviation 106.624	22.596 Milliliters (ml) per 28 days Standard Deviation 60.666

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Time to First Use of ESA Rescue Therapy during efficacy emergent period. For participants with use of ESA, the time to first use of ESA was calculated as (First event date - Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. Participants without ESA rescue were censored at the end of treatment.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Use of ESA Rescue Therapy Year 1	4.8 Percentage of participants Interval 2.4 to 7.2	36.4 Percentage of participants Interval 28.9 to 43.9
Time to First Use of ESA Rescue Therapy Year 0.5	1.8 Percentage of participants Interval 0.4 to 3.2	20.4 Percentage of participants Interval 14.5 to 26.3
Time to First Use of ESA Rescue Therapy Year 1.5	6.0 Percentage of participants Interval 3.1 to 8.9	42.3 Percentage of participants Interval 33.9 to 50.8
Time to First Use of ESA Rescue Therapy Year 2	6.7 Percentage of participants Interval 3.5 to 9.9	42.3 Percentage of participants Interval 33.9 to 50.8

SECONDARY outcome

Timeframe: Baseline to week 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Time to first use of IV iron during efficacy emergent period in years. For participants with use of IV iron, the time to first use of IV iron was calculated as (First event date - Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first.Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to First Use of IV Iron Year 0.5	2.3 Percentage of participants Interval 0.7 to 3.9	6.2 Percentage of participants Interval 2.7 to 9.8
Time to First Use of IV Iron Year 1	5.3 Percentage of participants Interval 2.8 to 7.8	9.4 Percentage of participants Interval 4.8 to 14.0
Time to First Use of IV Iron Year 1.5	7.5 Percentage of participants Interval 4.3 to 10.7	10.7 Percentage of participants Interval 5.5 to 15.9
Time to First Use of IV Iron Year 2	10.6 Percentage of participants Interval 6.3 to 14.8	19.1 Percentage of participants Interval 8.8 to 29.5

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 68, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline to each planned assessment for total cholesterol is reported. Baseline was defined as the value on day 1. If the value was missing, the latest value prior to first study drug administration was used.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 84	-1.055 mmol/L Standard Deviation 1.554	0.102 mmol/L Standard Deviation 1.284
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 104	-0.944 mmol/L Standard Deviation 1.584	0.218 mmol/L Standard Deviation 1.067
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 4	-1.151 mmol/L Standard Deviation 1.058	0.108 mmol/L Standard Deviation 0.842
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 8	-1.066 mmol/L Standard Deviation 1.086	0.048 mmol/L Standard Deviation 0.932
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 12	-0.836 mmol/L Standard Deviation 1.173	0.088 mmol/L Standard Deviation 1.116
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 20	-0.747 mmol/L Standard Deviation 1.227	0.193 mmol/L Standard Deviation 1.129
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 28	-0.816 mmol/L Standard Deviation 1.284	0.201 mmol/L Standard Deviation 1.271
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 36	-0.803 mmol/L Standard Deviation 1.300	0.183 mmol/L Standard Deviation 1.174
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 44	-0.854 mmol/L Standard Deviation 1.238	0.077 mmol/L Standard Deviation 1.346
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 52	-0.815 mmol/L Standard Deviation 1.314	0.104 mmol/L Standard Deviation 1.304
Change From BL to Each Post-Dosing Visit in Total Cholesterol Week 68	-0.971 mmol/L Standard Deviation 1.382	0.188 mmol/L Standard Deviation 1.222

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 68, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline to each planned assessment for LDL/HDL ratio is reported. Baseline was defined as the 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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 4	-0.331 Ratio Standard Deviation 0.777	0.076 Ratio Standard Deviation 0.635
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 8	-0.374 Ratio Standard Deviation 0.952	0.068 Ratio Standard Deviation 0.685
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 12	-0.268 Ratio Standard Deviation 0.905	0.081 Ratio Standard Deviation 0.915
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 20	-0.250 Ratio Standard Deviation 1.024	0.155 Ratio Standard Deviation 0.788
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 28	-0.313 Ratio Standard Deviation 1.057	0.156 Ratio Standard Deviation 0.861
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 36	-0.349 Ratio Standard Deviation 1.040	0.157 Ratio Standard Deviation 1.053
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 44	-0.368 Ratio Standard Deviation 1.099	0.099 Ratio Standard Deviation 1.198
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 52	-0.429 Ratio Standard Deviation 1.125	0.019 Ratio Standard Deviation 1.076
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 68	-0.466 Ratio Standard Deviation 1.219	0.052 Ratio Standard Deviation 0.955
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 84	-0.509 Ratio Standard Deviation 1.307	0.114 Ratio Standard Deviation 1.113
Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio Week 104	-0.414 Ratio Standard Deviation 1.306	0.105 Ratio Standard Deviation 0.873

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 68, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline to each planned assessment for non-HDL is reported. Baseline was defined as the 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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 52	-0.751 mmol/L Standard Deviation 1.276	0.104 mmol/L Standard Deviation 1.299
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 68	-0.882 mmol/L Standard Deviation 1.325	0.174 mmol/L Standard Deviation 1.187
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 4	-0.969 mmol/L Standard Deviation 0.989	0.118 mmol/L Standard Deviation 0.789
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 8	-0.909 mmol/L Standard Deviation 1.064	0.070 mmol/L Standard Deviation 0.864
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 12	-0.709 mmol/L Standard Deviation 1.107	0.078 mmol/L Standard Deviation 1.050
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 20	-0.638 mmol/L Standard Deviation 1.175	0.186 mmol/L Standard Deviation 1.072
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 28	-0.710 mmol/L Standard Deviation 1.227	0.206 mmol/L Standard Deviation 1.227
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 36	-0.711 mmol/L Standard Deviation 1.239	0.202 mmol/L Standard Deviation 1.133
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 44	-0.751 mmol/L Standard Deviation 1.190	0.106 mmol/L Standard Deviation 1.342
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 84	-0.939 mmol/L Standard Deviation 1.518	0.089 mmol/L Standard Deviation 1.343
Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol Week 104	-0.839 mmol/L Standard Deviation 1.554	0.174 mmol/L Standard Deviation 1.014

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 68, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline to each planned assessment for apolipoproteins A1 is reported. Baseline was defined as the 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=188 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=105 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 4	-0.168 g/L Standard Deviation 0.232	0.013 g/L Standard Deviation 0.190
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 8	-0.148 g/L Standard Deviation 0.229	0.008 g/L Standard Deviation 0.227
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 12	-0.131 g/L Standard Deviation 0.254	0.004 g/L Standard Deviation 0.203
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 20	-0.114 g/L Standard Deviation 0.245	0.036 g/L Standard Deviation 0.222
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 28	-0.104 g/L Standard Deviation 0.265	0.006 g/L Standard Deviation 0.233
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 36	-0.101 g/L Standard Deviation 0.252	0.002 g/L Standard Deviation 0.223
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 44	-0.135 g/L Standard Deviation 0.259	-0.013 g/L Standard Deviation 0.268
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 52	-0.090 g/L Standard Deviation 0.260	-0.028 g/L Standard Deviation 0.248
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 68	-0.157 g/L Standard Deviation 0.310	0.018 g/L Standard Deviation 0.204
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 84	-0.132 g/L Standard Deviation 0.282	0.060 g/L Standard Deviation 0.196
Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1) Week 104	-0.098 g/L Standard Deviation 0.227	0.070 g/L Standard Deviation 0.136

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 68, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline to each planned assessment for apolipoproteins B is reported. Baseline was defined as the 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=188 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=105 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 4	-19.891 mg/dL Standard Deviation 20.669	2.059 mg/dL Standard Deviation 22.220
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 8	-19.483 mg/dL Standard Deviation 21.009	2.059 mg/dL Standard Deviation 20.297
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 12	-14.935 mg/dL Standard Deviation 24.613	0.278 mg/dL Standard Deviation 21.707
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 20	-12.709 mg/dL Standard Deviation 24.424	5.711 mg/dL Standard Deviation 25.883
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 28	-13.782 mg/dL Standard Deviation 28.634	9.746 mg/dL Standard Deviation 26.864
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 36	-14.866 mg/dL Standard Deviation 25.469	6.623 mg/dL Standard Deviation 25.895
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 44	-15.593 mg/dL Standard Deviation 26.594	3.222 mg/dL Standard Deviation 30.771
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 52	-14.122 mg/dL Standard Deviation 27.503	4.676 mg/dL Standard Deviation 31.440
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 68	-18.746 mg/dL Standard Deviation 28.633	2.786 mg/dL Standard Deviation 28.900
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 84	-20.133 mg/dL Standard Deviation 28.134	12.500 mg/dL Standard Deviation 32.152
Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB) Week 104	-10.917 mg/dL Standard Deviation 22.885	14.750 mg/dL Standard Deviation 20.271

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 68, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Change from baseline to each planned assessment for ratio of ApoB/ApoA1 is reported. Baseline was defined as the 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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 68	-0.086 Ratio Standard Deviation 0.212	0.001 Ratio Standard Deviation 0.184
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 44	-0.053 Ratio Standard Deviation 0.220	0.031 Ratio Standard Deviation 0.265
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 52	-0.065 Ratio Standard Deviation 0.207	0.047 Ratio Standard Deviation 0.266
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 84	-0.066 Ratio Standard Deviation 0.210	0.058 Ratio Standard Deviation 0.295
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 104	-0.024 Ratio Standard Deviation 0.126	0.085 Ratio Standard Deviation 0.132
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 4	-0.073 Ratio Standard Deviation 0.165	0.010 Ratio Standard Deviation 0.169
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 8	-0.084 Ratio Standard Deviation 0.202	0.000 Ratio Standard Deviation 0.184
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 12	-0.059 Ratio Standard Deviation 0.164	-0.006 Ratio Standard Deviation 0.201
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 20	-0.043 Ratio Standard Deviation 0.189	0.009 Ratio Standard Deviation 0.198
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 28	-0.066 Ratio Standard Deviation 0.222	0.063 Ratio Standard Deviation 0.205
Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1 Week 36	-0.070 Ratio Standard Deviation 0.200	0.045 Ratio Standard Deviation 0.213

SECONDARY outcome

Timeframe: Weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Mean LDL cholesterol <100 mg/dL over weeks 12 to 28 was defined as a binary variable (Yes/No), where Yes was defined as mean LDL cholesterol <100 mg/dL over weeks 12 to 28. Participants without any LDL value within this duration were excluded.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28 Yes (Regardless of fasting status)	62.9 Percentage of Participants	41.1 Percentage of Participants
Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28 No (Regardless of fasting status)	37.1 Percentage of Participants	58.9 Percentage of Participants

SECONDARY outcome

Timeframe: Weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Occurrence of achieved antihypertensive treatment goal was defined as the average SBP < 130 mmHg and the average DBP < 80 mmHg over the period of weeks 12-28. Participants without any blood pressure measurement were excluded.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28 No	74.4 Percentage of Participants	72.0 Percentage of Participants
Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28 Yes	25.6 Percentage of Participants	28.0 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The 36-Item short-form health survey (SF-36) is a multi-purpose survey with 36 questions. It provides an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. For each scale scores range from 0-100. The physical component score was calculated based on the results of the SF-36 scores. Higher scores indicate better health status.

Outcome measures

Measure	Roxadustat n=340 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=185 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to the Average Value of Weeks 12-28 in Quality of Life (QoL) SF-36 Physical Component Score (PCS)	1.842 Units on a Scale Interval 0.88 to 2.8	1.468 Units on a Scale Interval 0.34 to 2.59

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

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 Anemia Subscale (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. For the above score, a higher score indicates better QoL.

Outcome measures

Measure	Roxadustat n=339 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=185 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to the Average Value of Weeks 12-28 in Anemia Subscale (Ans) of Functional Assessment of Cancer Therapy (FACT-An) Score	4.470 Units on a Scale Interval 2.86 to 6.08	2.766 Units on a Scale Interval 0.91 to 4.62

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Baseline FACT-An Total Score was defined as the FACT-An Total score 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 (PWB) - 7 items, functional (FWB) - 7 items, social/family (SWB) - 7 items, and emotional (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score is obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range is 0-188. A higher score indicates better QoL.

Outcome measures

Measure	Roxadustat n=338 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=185 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to the Average Value of Weeks 12-28 in Total FACT-An Score	5.777 Units on a Scale Interval 2.6 to 8.95	3.691 Units on a Scale Interval 0.01 to 7.37

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The Euroqol Questionnaire - 5 Dimensions 5 Levels (EQ-5D 5L) is a self-reported questionnaire. The EQ-5D 5L is used as a measure of respondents' Health Related Quality of Life (HRQoL). The EQ-5D 5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D 5L descriptive system comprises of 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 answers are labeled 'Best imaginable health state' and 'Worst imaginable health state' with higher scores for higher HRQoL.

Outcome measures

Measure	Roxadustat n=340 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=184 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to the Average Value of Weeks 12-28 in the Euroqol Questionnaire - 5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score	5.390 Units on a Scale Standard Deviation 17.278	0.990 Units on a Scale Standard Deviation 15.859

SECONDARY outcome

Timeframe: Baseline and weeks 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Work productivity and activity impairment: anemic symptoms (WPAI:ANS) questionnaire version 2 was used to measure work and activity impairment during the last seven days due to anemia. It is self-assessed questionnaire which consists of 6 questions covering work and daily activities. Questions include asking if participant is working, how many hours the person missed work due to anemic symptoms, how many hours the person missed work due to other reasons, how many hours participant actually worked and how the anemic symptoms impacted their productivity and ability to do daily activities. For the last 2 questions, they were scored from 0-10 with 0 identifying no effect on work and 10 completely prevented from working. Overall work impairment due to ANS was calculated as 100 x Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]. Scores were calculated with the formula to derive the overall work impairment on each timepoints in percentage, and then changes of the percentage from baseline are reported.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to the Average Value of Weeks 12-28 in Overall Work Impairment Due to Anaemic Symptoms	-5.965 Percentage of work impairment Standard Deviation 21.856	-4.230 Percentage of work impairment Standard Deviation 23.679

SECONDARY outcome

Timeframe: Week 12 to 28

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The Patients' Global Impression of Change (PGIC) is a participant-rated instrument that measures change in participants overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Percentage of Participants in Each Category in Patients' Global Impression of Change (PGIC) Week 12 [Very much improved + Much improved]	41.2 Percentage of Participants	18.9 Percentage of Participants
Percentage of Participants in Each Category in Patients' Global Impression of Change (PGIC) Week 28 [Very much improved + Much improved]	46.4 Percentage of Participants	28.6 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and weeks 4,12,20,36,52,104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Baseline was assessed on 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=382 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=195 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Serum Hepcidin Week 4	-19.835 ug/L Standard Deviation 29.765	1.748 ug/L Standard Deviation 35.368
Change From BL to Each Study Visit in Serum Hepcidin Week 12	-17.369 ug/L Standard Deviation 31.572	0.971 ug/L Standard Deviation 33.952
Change From BL to Each Study Visit in Serum Hepcidin Week 20	-10.684 ug/L Standard Deviation 35.858	-1.879 ug/L Standard Deviation 30.661
Change From BL to Each Study Visit in Serum Hepcidin Week 36	-12.981 ug/L Standard Deviation 32.351	0.803 ug/L Standard Deviation 39.816
Change From BL to Each Study Visit in Serum Hepcidin Week 52	-12.274 ug/L Standard Deviation 37.445	2.025 ug/L Standard Deviation 40.678
Change From BL to Each Study Visit in Serum Hepcidin Week 104	-10.051 ug/L Standard Deviation 33.671	-7.436 ug/L Standard Deviation 22.923

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Serum Ferritin Week 36	-142.876 pmol/L Standard Deviation 608.677	36.005 pmol/L Standard Deviation 538.357
Change From BL to Each Study Visit in Serum Ferritin Week 44	-137.151 pmol/L Standard Deviation 352.715	57.373 pmol/L Standard Deviation 594.125
Change From BL to Each Study Visit in Serum Ferritin Week 4	-221.827 pmol/L Standard Deviation 248.902	11.564 pmol/L Standard Deviation 335.096
Change From BL to Each Study Visit in Serum Ferritin Week 8	-247.955 pmol/L Standard Deviation 295.920	1.789 pmol/L Standard Deviation 309.673
Change From BL to Each Study Visit in Serum Ferritin Week 12	-265.812 pmol/L Standard Deviation 318.433	-21.098 pmol/L Standard Deviation 254.782
Change From BL to Each Study Visit in Serum Ferritin Week 20	-198.349 pmol/L Standard Deviation 284.015	-32.561 pmol/L Standard Deviation 320.382
Change From BL to Each Study Visit in Serum Ferritin Week 28	-184.501 pmol/L Standard Deviation 341.114	-5.123 pmol/L Standard Deviation 470.691
Change From BL to Each Study Visit in Serum Ferritin Week 52	164.009 pmol/L Standard Deviation 564.396	93.245 pmol/L Standard Deviation 640.998
Change From BL to Each Study Visit in Serum Ferritin Week 60	-133.499 pmol/L Standard Deviation 467.931	-18.833 pmol/L Standard Deviation 441.131
Change From BL to Each Study Visit in Serum Ferritin Week 68	-159.906 pmol/L Standard Deviation 453.802	39.794 pmol/L Standard Deviation 581.616
Change From BL to Each Study Visit in Serum Ferritin Week 76	-149.226 pmol/L Standard Deviation 408.126	25.291 pmol/L Standard Deviation 627.834
Change From BL to Each Study Visit in Serum Ferritin Week 84	-103.284 pmol/L Standard Deviation 530.021	93.647 pmol/L Standard Deviation 753.265
Change From BL to Each Study Visit in Serum Ferritin Week 92	-106.070 pmol/L Standard Deviation 464.192	1.011 pmol/L Standard Deviation 474.434
Change From BL to Each Study Visit in Serum Ferritin Week 100	-119.647 pmol/L Standard Deviation 452.209	30.829 pmol/L Standard Deviation 514.823
Change From BL to Each Study Visit in Serum Ferritin Week 104	-107.814 pmol/L Standard Deviation 458.702	4.524 pmol/L Standard Deviation 475.524

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Baseline was assessed on 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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 4	-7.4 Percentage saturated Standard Deviation 11.7	0.7 Percentage saturated Standard Deviation 11.4
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 8	-5.7 Percentage saturated Standard Deviation 11.7	-0.4 Percentage saturated Standard Deviation 13.0
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 68	-2.2 Percentage saturated Standard Deviation 13.1	-3.3 Percentage saturated Standard Deviation 12.3
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 12	-4.6 Percentage saturated Standard Deviation 13.5	-0.7 Percentage saturated Standard Deviation 11.5
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 20	-1.1 Percentage saturated Standard Deviation 13.4	-0.3 Percentage saturated Standard Deviation 11.5
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 28	-1.8 Percentage saturated Standard Deviation 13.8	0.8 Percentage saturated Standard Deviation 13.2
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 36	-1.6 Percentage saturated Standard Deviation 13.6	1.1 Percentage saturated Standard Deviation 14.6
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 44	-0.2 Percentage saturated Standard Deviation 14.0	1.0 Percentage saturated Standard Deviation 16.0
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 52	-0.7 Percentage saturated Standard Deviation 13.6	0.0 Percentage saturated Standard Deviation 16.3
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 60	-0.6 Percentage saturated Standard Deviation 14.1	-2.7 Percentage saturated Standard Deviation 13.9
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 76	-2.6 Percentage saturated Standard Deviation 13.8	-1.7 Percentage saturated Standard Deviation 13.9
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 84	-3.4 Percentage saturated Standard Deviation 13.3	-3.6 Percentage saturated Standard Deviation 13.8
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 92	-1.9 Percentage saturated Standard Deviation 13.2	-1.8 Percentage saturated Standard Deviation 12.8
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 100	0.0 Percentage saturated Standard Deviation 13.4	0.7 Percentage saturated Standard Deviation 12.0
Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT) Week 104	-0.4 Percentage saturated Standard Deviation 12.6	0.0 Percentage saturated Standard Deviation 12.3

SECONDARY outcome

Timeframe: Baseline and weeks 12, 28, 36, 44, 60, 84, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

HbA1c was measured at each timepoint and presented in 'fraction of 1' unit by dividing the values in percentage by 100, in order to fit for CDISC (Clinical Data Interchange Standards Consortium) standard terminology. Changes from baseline to each timepoint were reported in unit 'fraction of 1'. Baseline was assessed on 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=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Serum HbA1c Level Week 28	0.0006 Fraction of 1 Standard Deviation 0.0086	0.0008 Fraction of 1 Standard Deviation 0.0091
Change From BL to Each Study Visit in Serum HbA1c Level Week 36	0.0011 Fraction of 1 Standard Deviation 0.0098	0.0007 Fraction of 1 Standard Deviation 0.0075
Change From BL to Each Study Visit in Serum HbA1c Level Week 44	0.0018 Fraction of 1 Standard Deviation 0.0081	-0.0002 Fraction of 1 Standard Deviation 0.0074
Change From BL to Each Study Visit in Serum HbA1c Level Week 60	0.0009 Fraction of 1 Standard Deviation 0.0073	0.0012 Fraction of 1 Standard Deviation 0.0080
Change From BL to Each Study Visit in Serum HbA1c Level Week 12	0.0007 Fraction of 1 Standard Deviation 0.0064	-0.0001 Fraction of 1 Standard Deviation 0.0061
Change From BL to Each Study Visit in Serum HbA1c Level Week 84	0.0028 Fraction of 1 Standard Deviation 0.0085	0.0022 Fraction of 1 Standard Deviation 0.0111
Change From BL to Each Study Visit in Serum HbA1c Level Week 104	0.0014 Fraction of 1 Standard Deviation 0.0073	0.0004 Fraction of 1 Standard Deviation 0.0059

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Baseline was assessed on 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=323 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=163 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Fasting Blood Glucose Week 28	0.160 mmol/L Standard Deviation 3.489	0.045 mmol/L Standard Deviation 3.281
Change From BL to Each Study Visit in Fasting Blood Glucose Week 36	0.015 mmol/L Standard Deviation 2.991	-0.117 mmol/L Standard Deviation 2.812
Change From BL to Each Study Visit in Fasting Blood Glucose Week 104	0.125 mmol/L Standard Deviation 2.633	0.237 mmol/L Standard Deviation 3.938
Change From BL to Each Study Visit in Fasting Blood Glucose Week 4	0.107 mmol/L Standard Deviation 2.573	-0.076 mmol/L Standard Deviation 2.730
Change From BL to Each Study Visit in Fasting Blood Glucose Week 8	-0.103 mmol/L Standard Deviation 3.179	-0.162 mmol/L Standard Deviation 3.118
Change From BL to Each Study Visit in Fasting Blood Glucose Week 12	-0.100 mmol/L Standard Deviation 3.504	-0.153 mmol/L Standard Deviation 4.629
Change From BL to Each Study Visit in Fasting Blood Glucose Week 20	-0.302 mmol/L Standard Deviation 4.052	0.523 mmol/L Standard Deviation 2.981
Change From BL to Each Study Visit in Fasting Blood Glucose Week 44	0.073 mmol/L Standard Deviation 2.683	0.801 mmol/L Standard Deviation 3.416
Change From BL to Each Study Visit in Fasting Blood Glucose Week 52	0.048 mmol/L Standard Deviation 4.348	-0.086 mmol/L Standard Deviation 4.883
Change From BL to Each Study Visit in Fasting Blood Glucose Week 60	0.130 mmol/L Standard Deviation 2.907	1.190 mmol/L Standard Deviation 3.946
Change From BL to Each Study Visit in Fasting Blood Glucose Week 68	0.185 mmol/L Standard Deviation 2.831	0.698 mmol/L Standard Deviation 3.386
Change From BL to Each Study Visit in Fasting Blood Glucose Week 76	-0.015 mmol/L Standard Deviation 2.031	-0.671 mmol/L Standard Deviation 5.148
Change From BL to Each Study Visit in Fasting Blood Glucose Week 84	0.495 mmol/L Standard Deviation 3.117	0.435 mmol/L Standard Deviation 2.037
Change From BL to Each Study Visit in Fasting Blood Glucose Week 92	0.612 mmol/L Standard Deviation 2.494	-0.861 mmol/L Standard Deviation 3.298
Change From BL to Each Study Visit in Fasting Blood Glucose Week 100	0.405 mmol/L Standard Deviation 2.932	-0.699 mmol/L Standard Deviation 2.161

SECONDARY outcome

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

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Baseline assessment was the assessment from day 1 visit. If baseline value was missing, value from screening visit was used. In case of missing data, no imputation rules were applied. To compute the geometric mean of albumin/creatinine ratio in urine and associated 95% CI, the mean of log-transformed albumin/creatinine ratio in urine values (ratio) and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis.

Outcome measures

Measure	Roxadustat n=159 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=94 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 12	1.08 Ratio Interval 0.96 to 1.2	1.06 Ratio Interval 0.84 to 1.34
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 24	1.19 Ratio Interval 1.04 to 1.36	1.16 Ratio Interval 0.89 to 1.53
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 36	1.21 Ratio Interval 1.04 to 1.41	1.04 Ratio Interval 0.77 to 1.4
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 52	1.28 Ratio Interval 1.02 to 1.59	1.04 Ratio Interval 0.72 to 1.51
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 64	1.25 Ratio Interval 0.84 to 1.87	0.96 Ratio Interval 0.53 to 1.71
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 76	1.12 Ratio Interval 0.51 to 2.44	0.82 Ratio Interval 0.41 to 1.65
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 88	1.10 Ratio Interval 0.38 to 3.17	0.51 Ratio Interval 0.27 to 0.97
Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine Week 104	1.92 Ratio Interval 0.75 to 4.89	0.38 Ratio Interval 0.08 to 1.88

SECONDARY outcome

Timeframe: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

Baseline assessment was the 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. To compute the geometric mean of serum Cr (ratio) and associated 95% CI, the mean of log-transformed serum Cr (ratio) values and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 104	1.16 Ratio Interval 1.05 to 1.27	1.28 Ratio Interval 1.09 to 1.51
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 44	1.12 Ratio Interval 1.07 to 1.16	1.16 Ratio Interval 1.1 to 1.22
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 52	1.12 Ratio Interval 1.07 to 1.16	1.15 Ratio Interval 1.09 to 1.22
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 60	1.09 Ratio Interval 1.05 to 1.14	1.15 Ratio Interval 1.07 to 1.23
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 68	1.11 Ratio Interval 1.06 to 1.17	1.24 Ratio Interval 1.13 to 1.37
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 76	1.13 Ratio Interval 1.07 to 1.2	1.23 Ratio Interval 1.12 to 1.36
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 84	1.13 Ratio Interval 1.07 to 1.2	1.19 Ratio Interval 1.05 to 1.35
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 92	1.19 Ratio Interval 1.12 to 1.27	1.22 Ratio Interval 1.05 to 1.41
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 100	1.16 Ratio Interval 1.08 to 1.24	1.26 Ratio Interval 1.06 to 1.5
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 4	1.01 Ratio Interval 1.0 to 1.03	1.05 Ratio Interval 1.03 to 1.07
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 8	1.03 Ratio Interval 1.01 to 1.05	1.07 Ratio Interval 1.04 to 1.09
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 12	1.04 Ratio Interval 1.02 to 1.06	1.07 Ratio Interval 1.04 to 1.11
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 20	1.08 Ratio Interval 1.06 to 1.12	1.09 Ratio Interval 1.05 to 1.13
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 28	1.12 Ratio Interval 1.08 to 1.16	1.13 Ratio Interval 1.08 to 1.17
Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio Week 36	1.12 Ratio Interval 1.08 to 1.16	1.12 Ratio Interval 1.07 to 1.18

SECONDARY outcome

Timeframe: Baseline and year 0.5, year 1, year 1.5 and year 2

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

The endpoint was defined as time to doubling serum creatinine or chronic dialysis or renal transplant what ever came first. Time to event was defined as (First event date - Analysis date of first dose intake + 1) / 365.25. First event date was defined as date of dialysis or date of renal transplant (whichever occurred first) and analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Years 0.5	17.4 Percentage of participants Interval 13.4 to 21.4	17.8 Percentage of participants Interval 12.3 to 23.4
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Years 1	36.8 Percentage of participants Interval 31.6 to 42.1	35.4 Percentage of participants Interval 27.9 to 42.9
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Years 1.5	47.3 Percentage of participants Interval 41.4 to 53.1	48.2 Percentage of participants Interval 38.6 to 57.8
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline Years 2	55.0 Percentage of participants Interval 48.5 to 61.4	54.7 Percentage of participants Interval 43.8 to 65.6

SECONDARY outcome

Timeframe: Baseline and year 0.5, year 1, year 1.5 and year 2

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

CKD 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. The time to CKD progression was calculated (in years) as (First event date - Analysis date of first dose intake + 1) / 365.25. First event date was defined as first occurrence of serum creatinine being doubled compared with baseline, first occurrence of chronic dialysis or renal transplant, occurrence of participants who died (whichever occurred first). Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to CKD Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Years 2	58.9 Percentage of participants Interval 52.7 to 65.1	61.1 Percentage of participants Interval 50.5 to 71.7
Time to CKD Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Years 0.5	20.5 Percentage of participants Interval 16.3 to 24.7	20.0 Percentage of participants Interval 14.2 to 25.8
Time to CKD Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Years 1	40.3 Percentage of participants Interval 35.1 to 45.5	38.3 Percentage of participants Interval 30.7 to 45.8
Time to CKD Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death) Years 1.5	50.2 Percentage of participants Interval 44.5 to 55.9	50.5 Percentage of participants Interval 41.1 to 59.9

SECONDARY outcome

Timeframe: Baseline and year 0.5, year 1, year 1.5 and year 2

Population: The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

All eGFR values collected during the safety emergent period are considered, excluding those collected on or after initiation of dialysis (acute or chronic). The First event date was defined as First occurrence of 40% decrease in eGFR from baseline, first occurrence of chronic dialysis or renal transplant (whichever occurred first and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the analysis date of last dose or end of study (EOS), whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

Outcome measures

Measure	Roxadustat n=389 Participants Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 Participants Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Years 1.5	54.6 Percentage of participants Interval 48.9 to 60.4	62.8 Percentage of participants Interval 53.2 to 72.5
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Years 2	64.5 Percentage of participants Interval 64.5 to 70.7	67.0 Percentage of participants Interval 56.8 to 77.1
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Years 1	44.4 Percentage of participants Interval 39.0 to 49.8	44.0 Percentage of participants Interval 36.2 to 51.7
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant Years 0.5	20.7 Percentage of participants Interval 16.5 to 25.0	22.3 Percentage of participants Interval 16.2 to 28.4

Adverse Events

Roxadustat

Serious events: 241 serious events

Other events: 204 other events

Deaths: 45 deaths

Placebo

Serious events: 115 serious events

Other events: 103 other events

Deaths: 20 deaths

Serious adverse events

Measure	Roxadustat n=391 participants at risk Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 participants at risk Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Blood and lymphatic system disorders Anaemia	2.0% 8/391 • Number of events 10 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	3.4% 7/203 • Number of events 9 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Blood and lymphatic system disorders Haemorrhagic anaemia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Blood and lymphatic system disorders Heparin-induced thrombocytopenia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Blood and lymphatic system disorders Lymphadenopathy mediastinal	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Blood and lymphatic system disorders Nephrogenic anaemia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Blood and lymphatic system disorders Neutropenia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Acute coronary syndrome	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Acute left ventricular failure	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Acute myocardial infarction	1.5% 6/391 • Number of events 6 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Angina pectoris	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Angina unstable	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Arteriosclerosis coronary artery	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Atrial fibrillation	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	1.5% 3/203 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Atrial flutter	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Atrioventricular block complete	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiac arrest	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiac failure	0.77% 3/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiac failure acute	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiac failure chronic	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	1.5% 3/203 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiac failure congestive	0.26% 1/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardio-respiratory arrest	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiogenic shock	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Cardiopulmonary failure	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Coronary artery disease	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Left ventricular failure	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Myocardial infarction	2.0% 8/391 • Number of events 8 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	1.5% 3/203 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Myocardial ischaemia	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Cardiac disorders Ventricular tachycardia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Congenital, familial and genetic disorders Congenital cystic kidney disease	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Ear and labyrinth disorders Vertigo	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Endocrine disorders Goitre	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Endocrine disorders Hyperparathyroidism primary	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Endocrine disorders Hyperparathyroidism secondary	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Eye disorders Macular hole	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Eye disorders Retinal detachment	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Eye disorders Ulcerative keratitis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Constipation	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Diabetic gastroparesis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Diarrhoea	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Duodenal ulcer	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Enterocolitis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Gastric ulcer	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Gastric ulcer perforation	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Gastritis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Gastritis erosive	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Haemorrhagic erosive gastritis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Haemorrhoids	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Inguinal hernia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Intestinal perforation	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Large intestinal ulcer	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Nausea	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Oesophagitis	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Pancreatitis chronic	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Rectal haemorrhage	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Small intestinal obstruction	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Vomiting	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Asthenia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Catheter site haemorrhage	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Chest pain	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Death	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	1.5% 3/203 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Gait disturbance	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders General physical health deterioration	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Multiple organ dysfunction syndrome	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Non-cardiac chest pain	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Oedema peripheral	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Peripheral swelling	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Sudden cardiac death	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Sudden death	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Hepatobiliary disorders Hepatic mass	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Hepatobiliary disorders Steatohepatitis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Immune system disorders Allergy to arthropod bite	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Abscess limb	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Anal abscess	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Appendicitis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Appendicitis perforated	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Bronchitis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Bronchitis bacterial	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Bursitis infective	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Cellulitis	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Clostridium difficile colitis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Clostridium difficile infection	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Device related infection	1.0% 4/391 • Number of events 5 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Diabetic foot infection	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Enterobacter bacteraemia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Epididymitis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Erysipelas	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Escherichia urinary tract infection	0.51% 2/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Eye infection	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Gangrene	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Hepatic echinococciasis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Hepatitis B	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Infected skin ulcer	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Lower respiratory tract infection	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Meningoencephalitis herpetic	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Orchitis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Osteomyelitis	0.26% 1/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Otitis media acute	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Peritonitis	1.3% 5/391 • Number of events 6 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pneumonia	4.3% 17/391 • Number of events 21 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	5.9% 12/203 • Number of events 14 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pneumonia staphylococcal	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Postoperative wound infection	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pulmonary sepsis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pyelonephritis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pyelonephritis acute	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pyelonephritis chronic	1.3% 5/391 • Number of events 5 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Pyonephrosis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Sepsis	1.5% 6/391 • Number of events 6 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Septic shock	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Sinusitis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Tuberculosis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Urinary tract infection	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Urinary tract infection bacterial	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Vulvovaginitis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Arterial injury	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Arteriovenous fistula thrombosis	3.6% 14/391 • Number of events 17 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Concussion	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Craniocerebral injury	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Facial bones fracture	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Fall	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Fat embolism	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Hip fracture	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Postoperative wound complication	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Pubis fracture	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Investigations Blood bilirubin increased	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Investigations Blood creatinine increased	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Investigations Blood urea increased	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Investigations Glomerular filtration rate decreased	5.4% 21/391 • Number of events 23 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	5.4% 11/203 • Number of events 15 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Dehydration	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Diabetes mellitus	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Diabetic metabolic decompensation	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Fluid overload	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Gout	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hypercalcaemia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hyperglycaemia	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hyperkalaemia	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hypervolaemia	0.51% 2/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hypoglycaemia	0.51% 2/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Musculoskeletal and connective tissue disorders Gouty arthritis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Musculoskeletal and connective tissue disorders Joint contracture	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to the mediastinum	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic carcinoma of the bladder	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Cerebral haemorrhage	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Cerebrovascular accident	1.3% 5/391 • Number of events 5 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Dementia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Diabetic neuropathy	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Dizziness	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Epilepsy	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Haemorrhagic stroke	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Headache	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Hypertensive encephalopathy	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Hypoglycaemic coma	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Ischaemic stroke	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Loss of consciousness	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Myasthenic syndrome	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Partial seizures	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Sciatica	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Syncope	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Transient ischaemic attack	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Vascular encephalopathy	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Product Issues Device dislocation	0.26% 1/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Product Issues Device malfunction	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Psychiatric disorders Depression	0.26% 1/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Psychiatric disorders Disorientation	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Acute kidney injury	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Acute prerenal failure	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Azotaemia	2.6% 10/391 • Number of events 11 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	3.9% 8/203 • Number of events 10 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Calculus bladder	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders End stage renal disease	34.5% 135/391 • Number of events 135 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	30.5% 62/203 • Number of events 63 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Haematuria	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Nephrolithiasis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Oliguria	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Renal colic	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Urethral stenosis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Renal and urinary disorders Urinary retention	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Reproductive system and breast disorders Metrorrhagia	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Reproductive system and breast disorders Ovarian cyst torsion	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Hydrothorax	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.77% 3/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	1.5% 3/203 • Number of events 5 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.77% 3/391 • Number of events 3 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.99% 2/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Diabetic foot	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Eczema nummular	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Panniculitis	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Rash	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Skin ulcer	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Skin and subcutaneous tissue disorders Toxic skin eruption	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Surgical and medical procedures Hospitalisation	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Surgical and medical procedures Leg amputation	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Aortic stenosis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Blood pressure inadequately controlled	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Deep vein thrombosis	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Diabetic vascular disorder	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Extremity necrosis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Hypertension	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Hypertensive crisis	1.0% 4/391 • Number of events 4 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	2.5% 5/203 • Number of events 5 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Hypotension	0.00% 0/391 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.49% 1/203 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Peripheral arterial occlusive disease	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Peripheral artery stenosis	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Peripheral ischaemia	0.26% 1/391 • Number of events 1 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Peripheral vascular disorder	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Thrombophlebitis	0.51% 2/391 • Number of events 2 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	0.00% 0/203 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.

Other adverse events

Measure	Roxadustat n=391 participants at risk Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.	Placebo n=203 participants at risk Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
Blood and lymphatic system disorders Anaemia	4.1% 16/391 • Number of events 17 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	15.3% 31/203 • Number of events 45 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Diarrhoea	8.2% 32/391 • Number of events 38 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	3.0% 6/203 • Number of events 9 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Gastrointestinal disorders Nausea	8.7% 34/391 • Number of events 44 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	3.0% 6/203 • Number of events 6 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Asthenia	4.6% 18/391 • Number of events 22 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	5.4% 11/203 • Number of events 13 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
General disorders Oedema peripheral	11.3% 44/391 • Number of events 53 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	10.3% 21/203 • Number of events 22 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Infections and infestations Viral upper respiratory tract infection	9.7% 38/391 • Number of events 50 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	4.4% 9/203 • Number of events 15 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Investigations Glomerular filtration rate decreased	6.1% 24/391 • Number of events 25 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	6.4% 13/203 • Number of events 13 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hyperkalaemia	9.2% 36/391 • Number of events 48 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	6.4% 13/203 • Number of events 19 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Hyperuricaemia	2.3% 9/391 • Number of events 9 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	5.4% 11/203 • Number of events 11 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Metabolism and nutrition disorders Iron deficiency	6.6% 26/391 • Number of events 26 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	3.9% 8/203 • Number of events 10 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Nervous system disorders Headache	5.1% 20/391 • Number of events 21 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	4.9% 10/203 • Number of events 11 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.
Vascular disorders Hypertension	21.7% 85/391 • Number of events 138 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.	13.3% 27/203 • Number of events 44 • From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality The safety emergent period was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose of study drug.

Additional Information

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