Trial Outcomes & Findings for A Study of Intravenous Mircera for the Treatment of Anemia in Dialysis Patients. (NCT NCT00077766)

Last Updated: 2016-10-26

Results Overview

A time adjusted mean change in hemoglobin (Hb) concentration was calculated using an area under the curve approach, for both periods separately. Change in Hb concentration between the baseline (Week -4 to Week -1) and evaluation periods was calculated by subtracting the calculated average baseline Hb value from the average evaluation period Hb value. All blood samples for Hb measurements were taken prior to study drug administration. The analysis used the last observation carried forward (LOCF) for missing Hb values for correction of the impact of early drop outs. The baseline period was defined as Week -4 to Week -1. The evaluation period was defined as Week 29 to Week 36.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

313 participants

Primary outcome timeframe

Baseline (Week -4 to Week -1) and Evaluation Period (Week 29 to Week 36)

Results posted on

2016-10-26

Participant Flow

A total of 313 participants were randomized in this study conducted from 10 March 2004 to 31 August 2005 in 12 countries.

Participant milestones

Participant milestones
Measure	RO0503821 (1x/2 Weeks) Eligible participants were administered with RO0503821 (methoxy polyethylene glycol-epoetin beta \[Mircera\]) intravenously (IV), every 2 weeks during Week 1 through Week 52. The starting dose of RO0503821 (60, 100, or 180 microgram \[µg\]) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Overall Study STARTED	157	156
Overall Study COMPLETED	118	131
Overall Study NOT COMPLETED	39	25

Reasons for withdrawal

Reasons for withdrawal
Measure	RO0503821 (1x/2 Weeks) Eligible participants were administered with RO0503821 (methoxy polyethylene glycol-epoetin beta \[Mircera\]) intravenously (IV), every 2 weeks during Week 1 through Week 52. The starting dose of RO0503821 (60, 100, or 180 microgram \[µg\]) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	4	3
Overall Study Death	12	10
Overall Study Lost to Follow-up	2	0
Overall Study Protocol Violation	1	0
Overall Study Kidney Transplantation	9	5
Overall Study Transplantation	5	1
Overall Study Investigators Discretion	1	0
Overall Study Participant's decision	1	0
Overall Study Dialysis Discontinued	1	0
Overall Study Dialysis	0	1
Overall Study Enrolled in Nocturnal Hemodialysis Study	0	1
Overall Study Started Nocturnal Dialysis	0	1
Overall Study Stop Dialysis	0	1
Overall Study Participants Vacation	2	1

Baseline Characteristics

A Study of Intravenous Mircera for the Treatment of Anemia in Dialysis Patients.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RO0503821 (1x/2 Weeks) n=153 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Week 1 through Week 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=156 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.	Total n=309 Participants Total of all reporting groups
Age, Continuous	62.5 Years STANDARD_DEVIATION 15.72 • n=5 Participants	61.9 Years STANDARD_DEVIATION 14.74 • n=7 Participants	62.2 Years STANDARD_DEVIATION 15.21 • n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants	74 Participants n=7 Participants	130 Participants n=5 Participants
Sex: Female, Male Male	97 Participants n=5 Participants	82 Participants n=7 Participants	179 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Week -4 to Week -1) and Evaluation Period (Week 29 to Week 36)

Population: The per protocol population was all randomized and treated participants, except those who had not met criteria for stable baseline Hb,and adequate iron levels or had hemoglobinopathies/hemolysis, RBC transfusion/blood loss, \<5 recorded Hb values during evaluation or missed administrations of trial drugs in week 26 to 35.

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=123 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=126 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Mean Change in Hemoglobin Concentration (g/dL) From Baseline to Evaluation Period	0.05 gram per deciliter (g/dL) Standard Deviation 0.96	-0.10 gram per deciliter (g/dL) Standard Deviation 0.92

SECONDARY outcome

Timeframe: Baseline (Week -4 to Week -1) and Evaluation Period (Week 29 to Week 36)

Population: The Intent-to-Treat (ITT) population was defined as all randomized participants. Participants with available data at the time of evaluation were analyzed.

The average Hb of all values recorded during the evaluation period was calculated, and this average was subtracted from the average baseline Hb values for each participant. The number of participants maintaining their average Hb within +/- 1 g/dL of their average baseline Hb concentration is displayed. The evaluation period was defined as Week 29 to Week 36.

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=139 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=142 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Number of Participants Maintaining Average Hemoglobin Concentration During the Evaluation Period Within +-1 g/dL of Their Average Baseline Hemoglobin Concentration	91 Participants	102 Participants

SECONDARY outcome

Timeframe: Week 1 to Week 36

Population: The safety population was defined as all participants who received at least one dose of RO0503821 or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not.

A combined data of the number of participants who received Red Blood Cell (RBC) transfusions during the titration and evaluation periods is reported. A period of 28 weeks after the first dose of the study drug was used for dose titration and stabilization of Hb concentration. The dose titration period was followed by an 8-week evaluation period (weeks 29 to 36).

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=153 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=156 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Number of Participants With Red Blood Cell Transfusions During the Dose Titration and Evaluation Periods	19 Participants	16 Participants

SECONDARY outcome

Timeframe: Up to Week 52

Population: The safety population was defined as all participants who received at least one dose of RO0503821 or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not. Data from participants available at protocol specified assessment time points were included in the analysis (n).

A marked abnormality range was defined as above and/or below a value which was considered to be potentially clinically relevant. Marked laboratory abnormalities were analyzed according to the Roche specified limits for the reference range of the following laboratory parameters: White blood cells (WBC) (3.0- 18.0 10\^9/liter \[L\]), platelets (100 - 550 10\^9/L), (alanine aminotransferase \[(ALAT)\] (0 - 110 units per liter \[U/L\]), alkaline phosphatase (ALP) (0 - 220 U/L), aspartate aminotransferase (ASAT) (0 - 80 U/L), albumin \>= 30 g/L, phosphate (0.75 - 1.60 millimole per liter \[mmol/L\]), potassium (2.9 - 5.8 mmol/L), glucose (2.80 - 11.10 mmol/L).

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=152 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=154 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Number of Participants With Marked Laboratory Abnormalities Platelets, High; n=152,153	0 Participants	6 Participants
Number of Participants With Marked Laboratory Abnormalities Platelets, Low; n=152,153	6 Participants	4 Participants
Number of Participants With Marked Laboratory Abnormalities WBC, High; n=152,153	4 Participants	3 Participants
Number of Participants With Marked Laboratory Abnormalities WBC, Low; n=152,153	6 Participants	4 Participants
Number of Participants With Marked Laboratory Abnormalities ALAT, high; n=152,154	4 Participants	2 Participants
Number of Participants With Marked Laboratory Abnormalities ALP, High; n=152,154	6 Participants	11 Participants
Number of Participants With Marked Laboratory Abnormalities ASAT, High; n=148,151	7 Participants	5 Participants
Number of Participants With Marked Laboratory Abnormalities Albumin, Low; n=143,142	12 Participants	14 Participants
Number of Participants With Marked Laboratory Abnormalities Phosphate, High; n=152,154	60 Participants	61 Participants
Number of Participants With Marked Laboratory Abnormalities Phosphate, Low; n=152,154	9 Participants	13 Participants
Number of Participants With Marked Laboratory Abnormalities Potassium, High; n=152,154	38 Participants	31 Participants
Number of Participants With Marked Laboratory Abnormalities Potassium, Low; n=152,154	0 Participants	1 Participants
Number of Participants With Marked Laboratory Abnormalities Glucose (fasting), High; n=103,100	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Week 36, and Week 52

Blood pressure Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) was measured by manual assessment or automated reading throughout the study for every participant. Blood pressure was taken in the sitting position after at least 5 minutes rest. An appropriate -sized cuff was used and both systolic and diastolic blood pressures were recorded before dialysis (BD) and after dialysis (AD).

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=130 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=134 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in SBP, BD, at Week 36, n = 130, 134	-2 millimeters of mercury (mm Hg) Standard Deviation 23.0	-2 millimeters of mercury (mm Hg) Standard Deviation 24.3
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in DBP, BD, at Week 36, n = 130, 134	-0 millimeters of mercury (mm Hg) Standard Deviation 12.8	-2 millimeters of mercury (mm Hg) Standard Deviation 16.4
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in SBP, BD, at Week 52, n = 117, 130	2 millimeters of mercury (mm Hg) Standard Deviation 24.6	-4 millimeters of mercury (mm Hg) Standard Deviation 22.0
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in DBP, BD, at Week 52, n = 117,130	0 millimeters of mercury (mm Hg) Standard Deviation 12.4	-3 millimeters of mercury (mm Hg) Standard Deviation 16.0
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in SBP, AD, at Week 36, n = 130, 132	-3 millimeters of mercury (mm Hg) Standard Deviation 25.9	-3 millimeters of mercury (mm Hg) Standard Deviation 24.0
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in DBP, AD, at Week 36, n = 130, 132	-3 millimeters of mercury (mm Hg) Standard Deviation 13.6	-4 millimeters of mercury (mm Hg) Standard Deviation 14.2
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in SBP, AD, at Week 52, n = 116,129	-0 millimeters of mercury (mm Hg) Standard Deviation 26.9	-3 millimeters of mercury (mm Hg) Standard Deviation 25.0
Mean Change in Blood Pressure From Baseline at Week 36 and Week 52 Change in DBP, AD, at Week 52, n = 116,129	-1 millimeters of mercury (mm Hg) Standard Deviation 15.0	-4 millimeters of mercury (mm Hg) Standard Deviation 14.9

SECONDARY outcome

Timeframe: Baseline, Week 36, and Week 52

Change in pulse rate (beats per minute \[bpm\]) from baseline values includes only those participants with both a baseline (BL) value and a value for specified time period.

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=126 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=128 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Mean Change in Pulse Rate (Sitting) From Baseline at Week 36 and Week 52 Change From Baseline to Week 36, n=126, 128	-1 beats per minute Standard Deviation 11.9	1 beats per minute Standard Deviation 10.6
Mean Change in Pulse Rate (Sitting) From Baseline at Week 36 and Week 52 Change From Baseline to Week 52, n=112, 126	-1 beats per minute Standard Deviation 13.0	0 beats per minute Standard Deviation 13.5

SECONDARY outcome

Timeframe: Up to Week 52

Population: The safety population was defined as all participants who received at least one dose of RO0503821 or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not.

An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event in the investigator's judgment or requires intervention to prevent one or other of these outcomes. Overall deaths occurred in the study were reported.

Outcome measures

Outcome measures
Measure	RO0503821 (1x/2 Weeks) n=153 Participants Eligible participants were administered with RO0503821 IV, every 2 weeks during Weeks 1 through 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=156 Participants Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Number of Participants With Any Adverse Events, Any Serious Adverse Event, and Deaths Number of participants with any AEs	135 Participants	143 Participants
Number of Participants With Any Adverse Events, Any Serious Adverse Event, and Deaths Number of participants with any SAEs	71 Participants	75 Participants
Number of Participants With Any Adverse Events, Any Serious Adverse Event, and Deaths Number of deaths (all causes)	13 Participants	12 Participants

Adverse Events

RO0503821 (1x/2 Weeks)

Serious events: 71 serious events

Other events: 97 other events

Deaths: 0 deaths

Darbepoetin (1x/1-2 Weeks)

Serious events: 75 serious events

Other events: 93 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Roche Trial Information Hotline

Hoffmann-La Roche AG

Phone: +41 61 6878333

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	RO0503821 (1x/2 Weeks) n=153 participants at risk Eligible participants were administered with RO0503821 IV, every 2 weeks during Week 1 through Week 52. The starting dose of RO0503821 (60, 100, or 180 µg) was based on the dose of darbepoetin alfa at the time of randomization (\< 40, 40 to 80, or \> 80 µg per week, respectively).	Darbepoetin (1x/1-2 Weeks) n=156 participants at risk Eligible participants were administered with darbepoetin alfa IV, every week or every 2 weeks during Week 1 through Week 52.
Nervous system disorders Headache	5.2% 8/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.7% 12/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Gastrointestinal disorders Diarrhoea	15.0% 23/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	9.6% 15/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Gastrointestinal disorders Vomiting	6.5% 10/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	8.3% 13/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Gastrointestinal disorders Nausea	7.2% 11/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	4.5% 7/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Gastrointestinal disorders Constipation	5.9% 9/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	2.6% 4/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Gastrointestinal disorders Abdominal pain upper	5.2% 8/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	1.9% 3/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Infections and infestations Nasopharyngitis	12.4% 19/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	10.3% 16/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Infections and infestations Influenza	12.4% 19/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.1% 11/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Infections and infestations Upper respiratory tract infection	5.9% 9/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.1% 11/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Musculoskeletal and connective tissue disorders Back pain	6.5% 10/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.1% 11/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Musculoskeletal and connective tissue disorders Muscle spasms	5.9% 9/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	3.8% 6/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Musculoskeletal and connective tissue disorders Pain in extremity	4.6% 7/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	5.1% 8/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Vascular disorders Hypertension	7.8% 12/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.7% 12/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Vascular disorders Hypotension	5.2% 8/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	3.2% 5/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Vascular disorders Haematoma	1.3% 2/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	5.1% 8/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Injury, poisoning and procedural complications Wound	5.9% 9/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	3.8% 6/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	5.2% 8/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	3.8% 6/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Injury, poisoning and procedural complications Procedural hypotension	5.9% 9/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	0.64% 1/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Respiratory, thoracic and mediastinal disorders Cough	9.2% 14/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.7% 12/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Metabolism and nutrition disorders Fluid overload	7.8% 12/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	7.1% 11/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
General disorders Pyrexia	6.5% 10/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	3.8% 6/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Cardiac disorders Angina pectoris	5.9% 9/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	3.8% 6/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.
Psychiatric disorders Depression	5.2% 8/153 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.	0.64% 1/156 • Up to Week 52 AE is untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event is with any of the following outcomes: Death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity; congenital anomaly.