Trial Outcomes & Findings for Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis. (NCT NCT02792231)

Last Updated: 2021-11-22

Results Overview

ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). Comparisons were made to the previous rating (the last EDSS rating that did not occur during a relapse).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

955 participants

Primary outcome timeframe

Baseline up to 2.5 years

Results posted on

2021-11-22

Participant Flow

It was pre-specified in the protocol to combine the data from this study with study NCT02792218 (COMB157G2301) for some outcome measures. Please refer to NCT02792218 for Participant Flow information for participants from other study.

A total of 1280 patients were screened, of whom 955 patients were randomized into the study.

Participant milestones

Participant milestones
Measure	OMB 20 mg Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Overall Study STARTED	481	474
Overall Study COMPLETED	399	390
Overall Study NOT COMPLETED	82	84

Reasons for withdrawal

Reasons for withdrawal
Measure	OMB 20 mg Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Overall Study Patient/guardian decision	32	42
Overall Study Adverse Event	15	11
Overall Study Physician Decision	14	12
Overall Study Lack of Efficacy	7	9
Overall Study Lost to Follow-up	9	5
Overall Study Pregnancy	1	3
Overall Study Non-compliance with study treatment	2	1
Overall Study Protocol deviation	2	0
Overall Study Technical problems	0	1

Baseline Characteristics

Participants with data that met requirements for analysis were included

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	OMB 20 mg n=481 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=474 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)	Total n=955 Participants Total of all reporting groups
Age, Continuous	38.0 Years STANDARD_DEVIATION 9.28 • n=481 Participants	38.2 Years STANDARD_DEVIATION 9.47 • n=474 Participants	38.1 Years STANDARD_DEVIATION 9.37 • n=955 Participants
Sex: Female, Male Female	319 Participants n=481 Participants	319 Participants n=474 Participants	638 Participants n=955 Participants
Sex: Female, Male Male	162 Participants n=481 Participants	155 Participants n=474 Participants	317 Participants n=955 Participants
Race/Ethnicity, Customized Asian	21 Participants n=481 Participants	19 Participants n=474 Participants	40 Participants n=955 Participants
Race/Ethnicity, Customized Black or African American	13 Participants n=481 Participants	18 Participants n=474 Participants	31 Participants n=955 Participants
Race/Ethnicity, Customized White	418 Participants n=481 Participants	417 Participants n=474 Participants	835 Participants n=955 Participants
Race/Ethnicity, Customized Other	20 Participants n=481 Participants	14 Participants n=474 Participants	34 Participants n=955 Participants
Race/Ethnicity, Customized Unknown	9 Participants n=481 Participants	6 Participants n=474 Participants	15 Participants n=955 Participants
Number of relapses in the past 12 months prior to screening	1.3 Number of relapses STANDARD_DEVIATION 0.74 • n=481 Participants	1.3 Number of relapses STANDARD_DEVIATION 0.73 • n=474 Participants	1.3 Number of relapses STANDARD_DEVIATION 0.74 • n=955 Participants
Expanded Disability Status Scale (EDSS)	2.90 Score on a scale STANDARD_DEVIATION 1.343 • n=481 Participants • Participants with data that met requirements for analysis were included	2.86 Score on a scale STANDARD_DEVIATION 1.373 • n=473 Participants • Participants with data that met requirements for analysis were included	2.88 Score on a scale STANDARD_DEVIATION 1.358 • n=954 Participants • Participants with data that met requirements for analysis were included
Number of gadolinium-enhancing T1 lesions	1.6 T1 lesions STANDARD_DEVIATION 4.07 • n=469 Participants • Participants with data that met requirements for analysis were included	1.5 T1 lesions STANDARD_DEVIATION 4.07 • n=470 Participants • Participants with data that met requirements for analysis were included	1.5 T1 lesions STANDARD_DEVIATION 4.07 • n=939 Participants • Participants with data that met requirements for analysis were included

PRIMARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set

Outcome measures

Outcome measures
Measure	OMB 20 mg n=469 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=470 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Annualized Relapse Rate (ARR)	0.10 number of relapses in a year Interval 0.08 to 0.13	0.25 number of relapses in a year Interval 0.21 to 0.3

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set from combined studies

A 3-month confirmed disability worsening (3mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 3 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=944 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=932 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data Month 18 - from Kaplan Meier estimates	9.4 percentage of participants Interval 7.6 to 11.5	13.5 percentage of participants Interval 11.4 to 16.0
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data Month 24 - from Kaplan Meier estimates	10.9 percentage of participants Interval 8.8 to 13.4	15.0 percentage of participants Interval 12.6 to 17.7

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set

Outcome measures

Outcome measures
Measure	OMB 20 mg n=479 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=473 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 Month 18 - from Kaplan Meier estimates	9.3 percentage of participants Interval 6.9 to 12.5	13.2 percentage of participants Interval 10.3 to 16.7
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 Month 24 - from Kaplan Meier estimates	10.5 percentage of participants Interval 7.8 to 14.1	14.6 percentage of participants Interval 11.5 to 18.6

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set from combined studies

A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=944 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=932 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data Month 18- from Kaplan Meier estimates	7.8 percentage of participants Interval 6.2 to 9.7	10.7 percentage of participants Interval 8.9 to 13.0
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data Month 24 - from Kaplan Meier estimates	8.1 percentage of participants Interval 6.5 to 10.2	12.0 percentage of participants Interval 9.9 to 14.5

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set

Outcome measures

Outcome measures
Measure	OMB 20 mg n=479 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=473 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 Month 18- from Kaplan Meier estimates	8.0 percentage of participants Interval 5.9 to 11.0	10.0 percentage of participants Interval 7.5 to 13.2
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 Month 24 - from Kaplan Meier estimates	8.0 percentage of participants Interval 5.9 to 11.0	10.9 percentage of participants Interval 8.2 to 14.4

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set from combined studies

A 6-month confirmed disability improvement (6mCDI) was defined as a decrease from baseline EDSS sustained for at least 6 months. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=749 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=724 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data Month 18 - from Kaplan Meier estimates	10.1 percentage of participants Interval 8.1 to 12.6	7.6 percentage of participants Interval 5.8 to 9.8
6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data Month 24 - from Kaplan Meier estimates	11.0 percentage of participants Interval 8.8 to 13.7	8.2 percentage of participants Interval 6.3 to 10.6

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set

Outcome measures

Outcome measures
Measure	OMB 20 mg n=374 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=361 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 Month 18 - from Kaplan Meier estimates	11.1 percentage of participants Interval 8.2 to 14.8	8.1 percentage of participants Interval 5.6 to 11.6
6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 Month 24 - from Kaplan Meier estimates	12.3 percentage of participants Interval 9.1 to 16.5	8.1 percentage of participants Interval 5.6 to 11.6

SECONDARY outcome

Timeframe: Baseline, yearly up to 2.5 years

Population: Full analysis set

Total number of Gd-enhancing T1 lesions across all scans per patient adjusted for different number of scans due to variable follow-up time in study.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=438 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=433 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Number of Gadolinium-enhancing T1 Lesions Per MRI Scan	0.0317 lesions per scan Interval 0.021 to 0.048	0.5172 lesions per scan Interval 0.404 to 0.662

SECONDARY outcome

Timeframe: Baseline, yearly up to 2.5 years

Population: Full analysis set

Number of new/enlarging T2 lesions on last available MRI scan compared to baseline adjusted for different time of scans versus baseline due to variable follow up time in study

Outcome measures

Outcome measures
Measure	OMB 20 mg n=448 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=442 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) Month 12 n=422,410	0.94 T2 lesions per year Interval 0.8 to 1.11	4.41 T2 lesions per year Interval 3.83 to 5.08
Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) Month 24 n=90,76	0.72 T2 lesions per year Interval 0.51 to 1.02	3.72 T2 lesions per year Interval 2.68 to 5.18
Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) EOS n=448,442	0.64 T2 lesions per year Interval 0.55 to 0.75	4.16 T2 lesions per year Interval 3.64 to 4.75

SECONDARY outcome

Timeframe: Month 3, 12 and 24

Population: Full analysis set

The NfL concentration (geometric mean concentration) was estimated by treatment and time point with using a repeated measures model on the basis of all evaluable log-transformed NfL values.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=425 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=423 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Neurofilament Light Chain (NfL) Concentration in Serum Month 3 n=425,423	8.92 pg/mL Interval 8.62 to 9.23	10.02 pg/mL Interval 9.68 to 10.36
Neurofilament Light Chain (NfL) Concentration in Serum Month 12 n=406,406	7.06 pg/mL Interval 6.77 to 7.37	9.53 pg/mL Interval 9.13 to 9.95
Neurofilament Light Chain (NfL) Concentration in Serum Month 24 n=345,349	6.80 pg/mL Interval 6.47 to 7.13	8.99 pg/mL Interval 8.57 to 9.44

SECONDARY outcome

Timeframe: Baseline, Months 12 and 24

Population: Full analysis set

Percent change from baseline in brain volume loss (BVL) on all MRI scans adjusted for different time of scan versus baseline due to variable follow up time in study

Outcome measures

Outcome measures
Measure	OMB 20 mg n=437 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=433 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline	-0.29 percentage of brain volume loss Interval -0.35 to -0.23	-0.35 percentage of brain volume loss Interval -0.42 to -0.29

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set

A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system).

Outcome measures

Outcome measures
Measure	OMB 20 mg n=469 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=470 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Participants With Confirmed Relapse	16.51 percentage of participants Interval 13.18 to 20.57	32.68 percentage of participants Interval 28.1 to 37.79

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set

Outcome measures

Outcome measures
Measure	OMB 20 mg n=461 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=467 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment	0.096 number of relapses in a year Interval 0.05 to 0.14	0.241 number of relapses in a year Interval 0.16 to 0.32

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set from combined studies.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=944 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=932 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data Month 18 - from Kaplan Meier estimates	9.4 percentage of participants Interval 7.6 to 11.5	13.5 percentage of participants Interval 11.4 to 16.0
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data Month 24 - from Kaplan Meier estimates	10.9 percentage of participants Interval 8.8 to 13.4	15.0 percentage of participants Interval 12.6 to 17.7

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set from combined studies.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=944 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=932 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data Month 18- from Kaplan Meier estimates	7.8 percentage of participants Interval 6.2 to 9.7	10.7 percentage of participants Interval 8.9 to 13.0
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data Month 24 - from Kaplan Meier estimates	8.1 percentage of participants Interval 6.5 to 10.2	12.0 percentage of participants Interval 9.9 to 14.5

SECONDARY outcome

Timeframe: Baseline, every 6 months up to 2.5 years

Population: Full analysis set from combined studies

A 6-month confirmed cognitive decline was defined as a decrease from baseline of at least 4 points in SDMT score sustained for at least 6 months. Processing speed was measured by the Symbol Digit Modalities Test (SDMT) score. SDMT measures the time to pair abstract symbols with specific numbers. The test requires visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items in 90 seconds. (max=110, min=0). Higher scores indicate improvement. Lower scores indicate worsening. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint

Outcome measures

Outcome measures
Measure	OMB 20 mg n=930 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=917 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data Month 18 - from Kaplan Meier estimates	14.3 percentage of participants Interval 12.2 to 16.8	13.7 percentage of participants Interval 11.5 to 16.1
6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data Month 24 - from Kaplan Meier estimates	15.4 percentage of participants Interval 13.1 to 18.2	14.0 percentage of participants Interval 11.8 to 16.6

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set from combined studies.

A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. A 6-month confirmed cognitive decline (6mCCD) was defined as a 4-point worsening on Symbol Digit Modalities Test (SDMT) sustained for at least 6 months. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=941 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=930 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data Month 18 - from Kaplan Meier estimates	20.5 percentage of participants Interval 18.0 to 23.4	21.7 percentage of participants Interval 19.1 to 24.6
6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data Month 24 - from Kaplan Meier estimates	21.4 percentage of participants Interval 18.8 to 24.3	22.6 percentage of participants Interval 19.9 to 25.7

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Full analysis set from combined studies.

Processing speed is being measured by the Symbol Digit Modalities Test (SDMT) score. SDMT measures the time to pair abstract symbols with specific numbers. The test requires visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items in 90 seconds. (max=110, min=0). Higher scores indicate improvement. Lower scores indicate worsening. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=921 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=909 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data Month 6 n=921,909	1.02 scores Interval 0.46 to 1.59	0.64 scores Interval 0.07 to 1.2
Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data Month 12 n=879,863	1.82 scores Interval 1.22 to 2.41	1.70 scores Interval 1.1 to 2.3
Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data Month 18 n=849,808	2.84 scores Interval 2.24 to 3.45	2.05 scores Interval 1.44 to 2.67
Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data Month 24 n=492,468	3.50 scores Interval 2.8 to 4.2	2.39 scores Interval 1.67 to 3.11
Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data Month 30 n=156,117	3.53 scores Interval 2.39 to 4.68	2.97 scores Interval 1.67 to 4.28

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set from combined studies.

The patient is directed to walk 25 feet quickly and safely as possible from one marked end to the other. The time is calculated from the initiation of the patient instructed to begin, until the patient has reached the 25-foot mark. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=936 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=925 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data Month 18 - from Kaplan Meier estimates	11.0 percentage of participants Interval 9.1 to 13.3	10.4 percentage of participants Interval 8.5 to 12.6
6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data Month 24 - from Kaplan Meier estimates	11.4 percentage of participants Interval 9.5 to 13.8	10.6 percentage of participants Interval 8.7 to 12.9

SECONDARY outcome

Timeframe: Baseline, every 6 months up to 2.5 years

Population: Full analysis set from combined studies.

9-Hole Peg Test is a test of upper limb function. Participants place 9 pegs on pegboard and remove pegs and this is timed for each hand. Time recorded in seconds. Longer time indicates poorer upper limb function. 20% improvement is defined as 20% shorter time in seconds. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=932 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=920 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data Month 18 - from Kaplan Meier estimates	2.9 percentage of participants Interval 2.0 to 4.3	3.3 percentage of participants Interval 2.3 to 4.8
6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data Month 24 - from Kaplan Meier estimates	2.9 percentage of participants Interval 2.0 to 4.3	3.3 percentage of participants Interval 2.3 to 4.8

SECONDARY outcome

Timeframe: Baseline, every 3 months up to 2.5 years

Population: Full analysis set from combined studies.

A 6-month confirmed disability improvement (6mCDI) sustained until EOS was defined as a decrease from baseline EDSS sustained until EOS. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=749 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=724 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data Month 18 - from Kaplan Meier estimates	5.4 percentage of participants Interval 4.0 to 7.4	4.6 percentage of participants Interval 3.2 to 6.5
6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data Month 24 - from Kaplan Meier estimates	5.8 percentage of participants Interval 4.2 to 7.8	4.6 percentage of participants Interval 3.2 to 6.5

SECONDARY outcome

Timeframe: Month 12 up to 2.5 years

Population: Full analysis set

Number of new/enlarging T2 lesions on the last available MRI scan compared to Month 12 adjusted for different time of scans versus Month 12 due to variable follow up time in study.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=369 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=348 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS)	0.13 T2 lesions per year Interval 0.09 to 0.18	3.84 T2 lesions per year Interval 3.19 to 4.62

SECONDARY outcome

Timeframe: Baseline, Month 12, Month 24

Population: Full analysis set

Percent change from baseline in total T2 lesion volume

Outcome measures

Outcome measures
Measure	OMB 20 mg n=447 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=437 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Percent Change in T2 Lesion Volume Relative to Baseline Month 12 n=447,437	-2.4 percentage change in lesion volume Standard Deviation 8.66	10.1 percentage change in lesion volume Standard Deviation 38.57
Percent Change in T2 Lesion Volume Relative to Baseline Month 24 n=330,320	-2.6 percentage change in lesion volume Standard Deviation 9.34	17.8 percentage change in lesion volume Standard Deviation 53.48

SECONDARY outcome

Timeframe: Baseline, Month 12, Month 24

Population: Full analysis set.

NEDA-4 was defined as no 3-month confirmed disability worsening, no confirmed MS relapse, no new or enlarging T2 lesions compared to baseline, and the annualized rate of brain atrophy \>-0.04%.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=433 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=427 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
No Evidence of Disease Activity (NEDA-4) Month 12 n=433,427	23.8 percentage of participants Interval 19.8 to 27.8	17.8 percentage of participants Interval 14.2 to 21.4
No Evidence of Disease Activity (NEDA-4) Month 24 n=92,78	9.8 percentage of participants Interval 3.7 to 15.9	5.1 percentage of participants Interval 0.2 to 10.0

SECONDARY outcome

Timeframe: Baseline, every 6 months up to 2.5 years

Population: Full analysis set

MSIS-29 is a 29-item, self-administered questionnaire that includes 2 domains, physical and psychological. Responses are captured on a 4-point scale ranging from "not at all" (1) to "extremely" (4), where higher scores reflect greater impact on day to day life.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=473 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=461 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline Month 6 n=473,461	-2.20 scores on a scale Standard Error 0.652	-0.46 scores on a scale Standard Error 0.659
Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline Month 12 n=448,438	-2.47 scores on a scale Standard Error 0.698	-0.49 scores on a scale Standard Error 0.704
Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline Month 18 n=425,409	-2.29 scores on a scale Standard Error 0.784	1.53 scores on a scale Standard Error 0.794
Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline Month 24 n=235,238	-2.93 scores on a scale Standard Error 0.904	0.62 scores on a scale Standard Error 0.905
Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline Month 30 n=70,54	-2.49 scores on a scale Standard Error 1.270	1.44 scores on a scale Standard Error 1.397

SECONDARY outcome

Timeframe: Baseline, every 6 months up to 2.5 years

Population: Full analysis set

Outcome measures

Outcome measures
Measure	OMB 20 mg n=473 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=461 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline Month 6 n=473,461	-5.96 scores on a scale Standard Error 0.807	-3.77 scores on a scale Standard Error 0.816
Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline Month 12 n=448,436	-5.42 scores on a scale Standard Error 0.830	-3.88 scores on a scale Standard Error 0.839
Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline Month 18 n=423,409	-6.23 scores on a scale Standard Error 0.884	-2.51 scores on a scale Standard Error 0.896
Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline Month 24 n=234,238	-6.10 scores on a scale Standard Error 1.092	-3.12 scores on a scale Standard Error 1.090
Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline Month 30 n=70,54	-6.25 scores on a scale Standard Error 1.623	-4.75 scores on a scale Standard Error 1.797

SECONDARY outcome

Timeframe: Baseline up to 2.5 years

Population: Supportive sub-group analysis based on estimations from pooled data from this study and study COMB157G2301.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=871 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=841 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data High > median n=443,410	0.08 number of relapses in a year Interval 0.07 to 0.11	0.21 number of relapses in a year Interval 0.17 to 0.26
Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data Low <= median n=428,431	0.12 number of relapses in a year Interval 0.09 to 0.15	0.23 number of relapses in a year Interval 0.19 to 0.27

SECONDARY outcome

Timeframe: Baseline, yearly up to 2.5 years

Population: Supportive sub-group analysis based on estimations from pooled data from this study and study COMB157G2301.

Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate).

Outcome measures

Outcome measures
Measure	OMB 20 mg n=850 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=823 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data High > median n=432,402	0.95 T2 lesions per year Interval 0.82 to 1.11	5.28 T2 lesions per year Interval 4.61 to 6.03
Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data Low <= median n=418,421	0.39 T2 lesions per year Interval 0.33 to 0.47	3.02 T2 lesions per year Interval 2.64 to 3.46

SECONDARY outcome

Timeframe: Baseline, Months 12 and 24

Population: Supportive sub-group analysis based on estimations from pooled data from this study and study COMB157G2301.

Percent change from baseline in brain volume loss (BVL) on all MRI scans adjusted for different time of scan versus baseline due to variable follow up time in study.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=819 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg n=794 Participants Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Brain Volume Loss by NfL High-low Subgroups - Pooled Data High > median n=416,387	-0.32 percentage of brain volume loss Interval -0.38 to -0.26	-0.43 percentage of brain volume loss Interval -0.49 to -0.37
Brain Volume Loss by NfL High-low Subgroups - Pooled Data Low <= median n=403,407	-0.24 percentage of brain volume loss Interval -0.3 to -0.18	-0.29 percentage of brain volume loss Interval -0.35 to -0.22

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 12, 24, 48, 96

Population: Full analysis set

Summary statistics of pharmacokinetic (PK) concentrations from trough samples collected within a 7-day window prior or at day of dosing.

Outcome measures

Outcome measures
Measure	OMB 20 mg n=481 Participants Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14 mg Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Pharmacokinetic (PK) Concentrations of Ofatumumab Baseline n=325	0.00325 ug/mL Standard Deviation 0.031372	—
Pharmacokinetic (PK) Concentrations of Ofatumumab Week 4 n=346	1.26512 ug/mL Standard Deviation 0.964645	—
Pharmacokinetic (PK) Concentrations of Ofatumumab Week 12 n=257	0.20932 ug/mL Standard Deviation 0.287839	—
Pharmacokinetic (PK) Concentrations of Ofatumumab Week 24 n=243	0.38203 ug/mL Standard Deviation 0.433175	—
Pharmacokinetic (PK) Concentrations of Ofatumumab Week 48 n=240	0.59087 ug/mL Standard Deviation 0.594490	—
Pharmacokinetic (PK) Concentrations of Ofatumumab Week 96 n=304	1.13218 ug/mL Standard Deviation 0.991141	—

Adverse Events

OMB 20mg

Serious events: 42 serious events

Other events: 348 other events

Deaths: 0 deaths

TER 14mg

Serious events: 37 serious events

Other events: 322 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	OMB 20mg n=481 participants at risk Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)	TER 14mg n=474 participants at risk Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Gastrointestinal disorders Diarrhoea	5.8% 28/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	10.3% 49/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Gastrointestinal disorders Nausea	6.2% 30/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	6.8% 32/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
General disorders Fatigue	5.2% 25/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	6.8% 32/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
General disorders Injection site reaction	12.7% 61/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	5.5% 26/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Infections and infestations Influenza	5.6% 27/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	5.9% 28/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Infections and infestations Nasopharyngitis	18.3% 88/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	18.6% 88/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Infections and infestations Upper respiratory tract infection	10.8% 52/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	9.9% 47/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Infections and infestations Urinary tract infection	11.4% 55/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	7.2% 34/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Injury, poisoning and procedural complications Injection related reaction	24.7% 119/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	13.9% 66/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Investigations Blood immunoglobulin M decreased	6.4% 31/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	1.7% 8/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Musculoskeletal and connective tissue disorders Back pain	7.3% 35/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	5.1% 24/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Musculoskeletal and connective tissue disorders Pain in extremity	4.6% 22/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	6.3% 30/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Nervous system disorders Headache	14.3% 69/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	13.9% 66/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Psychiatric disorders Anxiety	6.2% 30/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	3.6% 17/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Psychiatric disorders Depression	4.8% 23/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	5.1% 24/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Skin and subcutaneous tissue disorders Alopecia	5.6% 27/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	15.8% 75/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Vascular disorders Hypertension	4.2% 20/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	6.8% 32/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Musculoskeletal and connective tissue disorders Arthralgia	6.2% 30/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	5.3% 25/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years
Respiratory, thoracic and mediastinal disorders Cough	3.5% 17/481 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years	5.1% 24/474 • Adverse events were reported from first dose of study treatment until last administration of study treatment plus 100 days post treatment, up to maximum duration of approximately 2.7 years