Trial Outcomes & Findings for Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of Amyotrophic Lateral Sclerosis (NCT NCT01753076)

Last Updated: 2017-12-21

Results Overview

The joint rank score is a combined assessment of function and survival. Function is assessed using change from Baseline in the ALSFRS-R total score. To calculate joint rank scores, every participant was compared with all other participants in a pair wise manner and assigned a score of -1, 0 or 1 based on their relative outcomes. A subject's joint rank score is the sum of their scores across the pair wise comparisons. The . The ALSFRS-R was a quickly administered (5 min) ordinal rating scale used to determine a participant's assessment of their capability and independence in 12 functional activities. There were 12 questions, graded by the participant 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing. Lower scores of ALSFRS-R reflect greater impairment.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

304 participants

Primary outcome timeframe

Week 48

Results posted on

2017-12-21

Participant Flow

A total of 304 participants were randomized (151 to placebo; 153 to ozanezumab 15 milligrams \[mg\]/kilogram \[kg\]), and 303 participants (151 placebo; 152 ozanezumab 15 mg /kg ) received at least one dose of investigational product (one of the participants who did not receive any study drug was re-randomized to ozanezumab).

Participant milestones

Participant milestones
Measure	Placebo Participants (par) received placebo once every 2 weeks by intravenous infusion up to Week 46.	Ozanezumab 15 mg/kg Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46.
Overall Study STARTED	151	152
Overall Study COMPLETED	110	106
Overall Study NOT COMPLETED	41	46

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants (par) received placebo once every 2 weeks by intravenous infusion up to Week 46.	Ozanezumab 15 mg/kg Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46.
Overall Study Adverse Event	17	18
Overall Study Lack of Efficacy	3	1
Overall Study Lost to Follow-up	2	1
Overall Study Physician Decision	4	2
Overall Study Withdrawal by Subject	14	24
Overall Study Other-Reached Protocol-defined Stopping	1	0

Baseline Characteristics

Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of Amyotrophic Lateral Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=151 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46.	Ozanezumab 15 mg/kg n=152 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46.	Total n=303 Participants Total of all reporting groups
Age, Continuous	55.5 Years STANDARD_DEVIATION 11.04 • n=5 Participants	55.7 Years STANDARD_DEVIATION 10.40 • n=7 Participants	55.6 Years STANDARD_DEVIATION 10.70 • n=5 Participants
Sex: Female, Male Female	54 Participants n=5 Participants	49 Participants n=7 Participants	103 Participants n=5 Participants
Sex: Female, Male Male	97 Participants n=5 Participants	103 Participants n=7 Participants	200 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	3 Participants n=5 Participants	8 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	5 Participants n=5 Participants	10 Participants n=7 Participants	15 Participants n=5 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	13 Participants n=5 Participants	5 Participants n=7 Participants	18 Participants n=5 Participants
Race/Ethnicity, Customized White - Arabic/North African Heritage	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	124 Participants n=5 Participants	121 Participants n=7 Participants	245 Participants n=5 Participants
Race/Ethnicity, Customized Mixed Race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 48

Population: ITT population. Only on-treatment data (data within 21 days of the last dose) were analyzed.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=152 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Joint Rank Scores for Combined Analysis of Function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised [ALSFRS-R] Score) and 48 Week Overall Survival	15.0 Scores on a scale Standard Error 13.58	-14.9 Scores on a scale Standard Error 13.54

SECONDARY outcome

Timeframe: Baseline and Week 48

Population: ITT Population. Only on-treatment data (data within 21 days of the last dose) were analyzed.

The rate of decline was estimated by the change from Baseline in ALSFRS-R. The monthly slope for the ALSFRS-R score (i.e., the monthly rate of decline) was calculated as change from Baseline in the ALSFRS-R score at the last visit for that treatment period divided by the study day at the last visit for that treatment period /30.4. The Week 0 (Visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. The ALSFRS-R was a quickly administered (5 min) ordinal rating scale used to determine a participant's assessment of their capability and independence in 12 functional activities. There were 12 questions, graded by the participant 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing.

Outcome measures

Outcome measures
Measure	Placebo n=104 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=101 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Change From Baseline in the ALSFRS-R Total Score at Week 48	-9.1 Scores on a scale Standard Error 0.64	-10.4 Scores on a scale Standard Error 0.64

SECONDARY outcome

Timeframe: Baseline to Week 48

Population: ITT Population. Only on-treatment data (data within 21 days of the last dose) were analyzed..

The rate of decline was estimated by the change from Baseline in ALSFRS-R. The monthly slope for the ALSFRS-R score (i.e., the monthly rate of decline) was calculated as change from Baseline in the ALSFRS-R score at the last visit for that treatment period divided by the study day at the last visit for that treatment period devided by 30.4. The Week 0 (Visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. The ALSFRS-R was a quickly administered (5 min) ordinal rating scale used to determine a participant's assessment of their capability and independence in 12 functional activities. There were 12 questions, graded by the participant 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing.

Outcome measures

Outcome measures
Measure	Placebo n=149 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=150 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Rate of Decline Over Week 48 in the ALSFRS-R Total Score	-0.84 change in scores on a scale per month Standard Error 0.063	-0.96 change in scores on a scale per month Standard Error 0.062

SECONDARY outcome

Timeframe: Baseline and Week 48

Population: ITT population. Only those participants available at indicated time points were analyzed.

SVC was measured by using a validated spirometer. Three SVC measurements were performed for each participant at each assessment provided the difference from the second trial (if arranged by the numerical value) was not greater than 10%. If the difference between the best and the next best (based on the largest numerical value) SVC value from the first three trials was greater than 10%, additional trials (up to 5 in total) could have been performed. The Week 0 (visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A mixed-model repeated measures (MMRM) adjusted for treatment, visit, treatment by visit, Baseline SVC, Baseline SVC by visit, riluzole use. and country group was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=96 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=98 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Change From Baseline in Slow Vital Capacity (SVC) at Week 48	-0.899 Liters (L) Standard Error 0.0804	-1.026 Liters (L) Standard Error 0.0804

SECONDARY outcome

Timeframe: Baseline and Week 48

Population: ITT Population. Only participants with data available at the specified time points were analyzed.

The HHD is a device placed between the hand of the practitioner and the tested body part and provides a quantified measurement of muscle strength. Each muscle was tested twice, and both values were recorded. Additionally, a third trial could have been performed if the variability between the first two trials was greater than 15 % or if the rater thought that one of the first two trials was not valid. The Week 0 (Visit 2) value was considered to be the Baseline value. Percent change from Baseline for each muscle group was calculated as 100\*(HHD score minus the Baseline score) divided by the Baseline score. The average percent change was the mean percent change across the muscle groups that were non-missing/non-zero at Baseline. MMRM adjusted for treatment, visit, treatment by visit, number of non-missing/non-zero muscle groups at Baseline, number of non-missing/non-zero muscle groups at Baseline by Visit, riluzole use, and country group was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=95 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Change From Baseline in Muscle Strength as Measured by Hand Held Dynamometry (HHD) Score at Week 48	-34.7 Percent change Standard Error 3.77	-42.9 Percent change Standard Error 3.75

SECONDARY outcome

Timeframe: Week 48

Population: ITT Population. Only participants with data available at the specified time points were analyzed.

The CGI-I scale is a single observer-rated item measuring global improvement relative to Baseline. The CGI-I score is rated on a 7-point scale, from 1 (very much improved) to 7 (very much worse). Participant status at Baseline was assessed using the Clinical Global Impression Severity scale (CGI-S), which is a 7-point scale (1: normal, not at all ill; 7: most extremely ill) used to rate the severity of the participant's illness. Participants achieving a score of 1-4 in the CGI-I at Week 48 were considered to be responders. A a logistic regression adjusted for CGI-S at Baseline, riluzole use, and world region was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=101 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=97 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Number of Clinical Global Impression-improvement Scale (CGI-I) Responders at Week 48	23 Participants	18 Participants

SECONDARY outcome

Timeframe: Week 48 and Week 60

Population: ITT Population

Overall survival is defined as the time from randomization to death or censoring at the time point of analysis, whichever comes first. Kaplan Meier estimates at Week 48 were evaluated at Day 344. A participant was considered to have completed if he/she was censored at Day 344. Kaplan Meier estimates at Week 60 were evaluated at Day 428. A participant was considered to have completed if he/she was censored at Day 428. Confidence intervals were estimated using the Brookmeyer Crowley method. Results are shown as the estimated percentage of participants alive at Weeks 48 and 60. Week 48: Only on-treatment data (data within 21 days of the last dose) were analyzed. Week 60: Including off treatment data (data after 21 days after the last dose) were analyzed.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=152 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Overall Survival at Week 48 and Week 60 Week 48	95.5 Percentage of participants Interval 92.0 to 99.0	94.3 Percentage of participants Interval 90.4 to 98.1
Overall Survival at Week 48 and Week 60 Week 60	87.4 Percentage of participants Interval 81.5 to 93.3	85.4 Percentage of participants Interval 79.4 to 91.3

SECONDARY outcome

Timeframe: Week 48

Population: ITT Population. Only on-treatment data (data within 21 days of the last dose) were analyzed.

Progression-free survival at Week 48 is defined as the time from randomization to progression (decline of at least six points on the ALSFRS-R from Baseline) or death or censored at Week 48, whichever comes first. Kaplan Meier estimates at Week 48 were evaluated at Day 344. A participant was considered to have completed if he/she was censored at Day 344. Confidence intervals were estimated using the Brookmeyer Crowley method. Results are shown as the estimated percentage of participants alive and without disease progression at Week 48.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=152 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Progression-free Survival at Week 48	30.8 Percentage of participants surviving Interval 23.0 to 38.6	28.5 Percentage of participants surviving Interval 21.1 to 35.9

SECONDARY outcome

Timeframe: Baseline and Week 48

Population: ITT Population. Only participants with data available at the specified time points were analyzed.

A utility score for each participant was calculated based on the value set for England. The Week 0 (Visit 2) value was considered to be the Baseline value. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. EQ-5D-5L is a standardized, participant-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-Visual Analog Scale (EQ-VAS). The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). . For each of these dimensions, the participant self assigned a score: 1 (no problems); 2 (slight problems); 3 (moderate problems); 4 (severe problems); 5 (extreme problems).Minimum score on scale was 1 and maximum score was 5 for each dimension. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=102 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Change From Baseline in the EuroQol 5 Dimensions-5 Level Short Form (EQ-5D-5L) Utility Score at Week 48	-0.234 Scores on a scale Standard Error 0.0207	-0.238 Scores on a scale Standard Error 0.0207

SECONDARY outcome

Timeframe: Baseline and Week 48

Population: ITT Population. Only participants with data available at the specified time points were analyzed

The ALSAQ-40 is a disease specific health status assessment for individuals with ALS/motor neuron disease. The ALSAQ-40 is comprised of 40 questions measuring 5discrete dimensions of health status that are affected by the disease: physical mobility (10 items); activities of daily living and independence (10 items); eating and drinking (3 items); communication (7 items); emotional reactions (10 items). Participants were asked to indicate the frequency of each event by selecting one of five options (Likert scale: 0-4): never/rarely/sometimes/often/ always or cannot do at all. The total score (minimum possible score=0, maximum possible score=160) was calculated by adding the five domain scores. A low score indicates a better health state. Change from Baseline was calculated by subtracting the derived Baseline value from the post-Baseline value. A mixed-model repeated measures adjusted for treatment, Visit, Treatment by Visit, and Baseline ALSAQ-40 total score was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=102 Participants Participants received placebo once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.	Ozanezumab 15 mg/kg n=96 Participants Participants received ozanezumab 15 milligrams per kilogram (mg/kg) once every 2 weeks by intravenous infusion up to Week 46. Final outcome assessment conducted at Week 48.
Change From Baseline in the Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) Total Score at Week 48	19.2 Scores on a scale Standard Error 1.47	20.6 Scores on a scale Standard Error 1.49

Adverse Events

Placebo

Serious events: 46 serious events

Other events: 119 other events

Deaths: 13 deaths

Ozanezumab IV

Serious events: 47 serious events

Other events: 120 other events

Deaths: 18 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=151 participants at risk Participants received placebo once every 2 weeks by intravenous infusion up to Week 46.	Ozanezumab IV n=152 participants at risk Participants received ozanezumab 15 mg/kg once every 2 weeks by intravenous infusion up to Week 46.
Injury, poisoning and procedural complications Fall	45.0% 68/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	36.8% 56/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Injury, poisoning and procedural complications Contusion	11.9% 18/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	7.2% 11/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	7.9% 12/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	16.4% 25/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Gastrointestinal disorders Constipation	7.9% 12/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	15.1% 23/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Gastrointestinal disorders Nausea	7.3% 11/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	9.2% 14/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Gastrointestinal disorders Dyspepsia	2.6% 4/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	6.6% 10/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Gastrointestinal disorders Vomiting	5.3% 8/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	3.3% 5/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Infections and infestations Nasopharyngitis	21.2% 32/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	23.0% 35/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Infections and infestations Urinary tract infection	6.6% 10/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	3.3% 5/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Infections and infestations Bronchitis	5.3% 8/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	3.9% 6/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Nervous system disorders Headache	17.2% 26/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	19.1% 29/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Nervous system disorders Dizziness	9.3% 14/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	10.5% 16/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	5.3% 8/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	8.6% 13/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Arthralgia	6.0% 9/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	7.2% 11/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Pain in extremity	4.6% 7/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	8.6% 13/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.0% 6/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	7.2% 11/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
General disorders Fatigue	8.6% 13/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	7.2% 11/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
General disorders Oedema peripheral	7.9% 12/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	7.9% 12/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
General disorders Peripheral swelling	4.6% 7/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	5.3% 8/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Cough	13.2% 20/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	11.2% 17/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Psychiatric disorders Anxiety	6.0% 9/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	4.6% 7/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Psychiatric disorders Depression	3.3% 5/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	7.2% 11/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Vascular disorders Haematoma	6.6% 10/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	3.3% 5/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Vascular disorders Hypertension	5.3% 8/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	2.6% 4/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.
Skin and subcutaneous tissue disorders Pruritus	3.3% 5/151 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.	5.3% 8/152 • Up to Week 64 AEs and SAEs were collected in members of the Safety Population, comprised of all participants in the treatment cohort who gave informed consent, were randomized, and received at least one dose of study medication.