ASCLEPIOS II: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02792231
• Collaborator: (none)
• Enrollment: 955
• Locations: 178
• Arms: 2
• Actual Duration (Months): 49.9
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To compare the efficacy and safety of ofatumumab administered subcutaneously (sc) every 4 weeks versus teriflunomide administered orally once daily in patients with relapsing multiple sclerosis

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Scelrosis	Drug: Ofatumumab subcutaneous injection; Drug: Teriflunomide-matching placebo capsules; Drug: Teriflunomide capsule; Drug: Matching placebo of ofatumumab subcutaneous injections	Phase 3

Detailed Description

This was a randomized, double-blind, double-dummy, active comparatorcontrolled, parallel-group, multi-center study with variable treatment duration in approximately 900 patients with relapsing multiple sclorosis (RMS). The maximal treatment duration in the study for an individual patient was 2.5 years. Eligible patients were randomized to receive either experimental ofatumumab subcutaneous (s.c.) injections every 4 weeks or active comparator teriflunomide orally once daily. The dose regimen for ofatumumab for this study was a loading dose regimen of 20 mg at Day 1, Day 7 and Day 14, followed by a maintenance dose regimen of 20 mg administered every 4 weeks starting at Week 4. In order to blind for the different formulations, double-dummy masking was used, i.e., all patients will take injections (containing either active ofatumumab or placebo) and oral capsules (containing either active teriflunomide or placebo).

Study Design

• Study Type: Interventional
• Actual Enrollment: 955 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Ofatumumab Versus Teriflunomide in Patients With Relapsing Multiple Sclerosis.
• Actual Study Start Date: Aug 26, 2016
• Actual Primary Completion Date: Jul 10, 2019
• Actual Study Completion Date: Oct 22, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OMG 20 mg Ofatumumab 20 mg pre-filled syringes for subcutaneous injectionon on days 1 ,7 ,14, week 4 and every 4 weeks thereafter and a teriflunomide-matching placebo, taken orally once daily	Drug: Ofatumumab subcutaneous injection; Ofatumumab 20 mg prefilled syringes for subcutaneous injection on days 1, 7, 14, week 4 and every 4 weeks thereafter; Drug: Teriflunomide-matching placebo capsules; Placebo capsule, matching in appearance to teriflunomide, taken orally once daily
Active Comparator: TER 14 mg Teriflunomide 14 mg oral capsule taken once daily and matching placebo for subcutaneous injections to ofatumumab on days 1, 7, 14, week 4 and every 4 weeks thereafter	Drug: Teriflunomide capsule; Teriflunomide 14 mg oral capsule taken once daily; Drug: Matching placebo of ofatumumab subcutaneous injections; Matching placebo of ofatumumab subcutaneous injections on days 1, 7, 14, week 4 and every 4 weeks thereafter

Outcome Measures

Primary Outcome Measures

1. Annualized Relapse Rate (ARR) [Baseline up to 2.5 years]

   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).

Secondary Outcome Measures

1. 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data [Baseline, every 3 months up to 2.5 years]

   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.

2. 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 [Baseline, every 3 months up to 2.5 years]

   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.

3. 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data [Baseline, every 3 months up to 2.5 years]

   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.

4. 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 [Baseline, every 3 months up to 2.5 years]

   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.

5. 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data [Baseline, every 3 months up to 2.5 years]

   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.

6. 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 [Baseline, every 3 months up to 2.5 years]

   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.

7. Number of Gadolinium-enhancing T1 Lesions Per MRI Scan [Baseline, yearly up to 2.5 years]

   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.

8. Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) [Baseline, yearly up to 2.5 years]

   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

9. Neurofilament Light Chain (NfL) Concentration in Serum [Month 3, 12 and 24]

   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.

10. Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline [Baseline, Months 12 and 24]

    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

11. Participants With Confirmed Relapse [Baseline up to 2.5 years]

    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).

12. Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment [Baseline up to 2.5 years]

    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).

13. 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data [Baseline up to 2.5 years]

    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.

14. 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data [Baseline up to 2.5 years]

    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.

15. 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data [Baseline, every 6 months up to 2.5 years]

    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

16. 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data [Baseline up to 2.5 years]

    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.

17. Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data [Baseline up to 2.5 years]

    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.

18. 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data [Baseline, every 3 months up to 2.5 years]

    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.

19. 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data [Baseline, every 6 months up to 2.5 years]

    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.

20. 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data [Baseline, every 3 months up to 2.5 years]

    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.

21. Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS) [Month 12 up to 2.5 years]

    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.

22. Percent Change in T2 Lesion Volume Relative to Baseline [Baseline, Month 12, Month 24]

    Percent change from baseline in total T2 lesion volume

23. No Evidence of Disease Activity (NEDA-4) [Baseline, Month 12, Month 24]

    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%.

24. Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline [Baseline, every 6 months up to 2.5 years]

    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.

25. Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline [Baseline, every 6 months up to 2.5 years]

    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.

26. Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data [Baseline up to 2.5 years]

    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).

27. Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data [Baseline, yearly up to 2.5 years]

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

28. Brain Volume Loss by NfL High-low Subgroups - Pooled Data [Baseline, Months 12 and 24]

    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.

29. Pharmacokinetic (PK) Concentrations of Ofatumumab [Baseline, Weeks 4, 12, 24, 48, 96]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female patients aged 18 to 55 years at Screening

• Diagnosis of multiple sclerosis (MS)

• Relapsing MS: relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) with disease activity

• Documentation of at least: 1 relapse during the previous 1 year OR 2 relapses during the previous 2 years OR a positive gadolinium-enhancing MRI scan during the year prior to randomization

• Disability status at Screening with an Expanded Disability Status Scale (EDSS) score of 0 to 5.5

• Neurologically stable within 1 month prior to randomization

Exclusion Criteria:

• Patients with primary progressive MS or SPMS without disease activity

• Disease duration of more than 10 years in patients with an EDSS score of 2 or less

• Patients with an active chronic disease of the immune system other than MS

• Patients at risk of developing or having reactivation of hepatitis

• Patients with active systemic infections or with neurological findings consistent with PML

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35233-0271
2	Novartis Investigative Site	Cullman	Alabama	United States	35058
3	Novartis Investigative Site	Tucson	Arizona	United States	85704
4	Novartis Investigative Site	Aurora	Colorado	United States	80045
5	Novartis Investigative Site	Basalt	Colorado	United States	81621
6	Novartis Investigative Site	Boulder	Colorado	United States	80301
7	Novartis Investigative Site	Centennial	Colorado	United States	80112
8	Novartis Investigative Site	Colorado Springs	Colorado	United States	80907
9	Novartis Investigative Site	Denver	Colorado	United States	80210
10	Novartis Investigative Site	Fort Collins	Colorado	United States	80528
11	Novartis Investigative Site	Fort Collins	Colorado	United States	907-280528
12	Novartis Investigative Site	Fairfield	Connecticut	United States	06824
13	Novartis Investigative Site	Newark	Delaware	United States	19713
14	Novartis Investigative Site	Bradenton	Florida	United States	34205
15	Novartis Investigative Site	Gainesville	Florida	United States	32611
16	Novartis Investigative Site	Maitland	Florida	United States	32751
17	Novartis Investigative Site	Ocala	Florida	United States	34471
18	Novartis Investigative Site	Oldsmar	Florida	United States	34677
19	Novartis Investigative Site	Ormond Beach	Florida	United States	32174
20	Novartis Investigative Site	Palm Coast	Florida	United States	32164
21	Novartis Investigative Site	Saint Petersburg	Florida	United States	33713
22	Novartis Investigative Site	Sarasota	Florida	United States	34243
23	Novartis Investigative Site	Tallahassee	Florida	United States	32312
24	Novartis Investigative Site	Tampa	Florida	United States	33603
25	Novartis Investigative Site	Tampa	Florida	United States	33609
26	Novartis Investigative Site	Tampa	Florida	United States	33612
27	Novartis Investigative Site	Suwanee	Georgia	United States	30024
28	Novartis Investigative Site	Anderson	Indiana	United States	46011
29	Novartis Investigative Site	Indianapolis	Indiana	United States	46256
30	Novartis Investigative Site	Wellesley	Massachusetts	United States	02481
31	Novartis Investigative Site	Detroit	Michigan	United States	48202
32	Novartis Investigative Site	Golden Valley	Minnesota	United States	55422
33	Novartis Investigative Site	Billings	Montana	United States	59101
34	Novartis Investigative Site	Great Falls	Montana	United States	59405
35	Novartis Investigative Site	Albuquerque	New Mexico	United States	87131-0001
36	Novartis Investigative Site	Asheville	North Carolina	United States	28806
37	Novartis Investigative Site	Charlotte	North Carolina	United States	28202
38	Novartis Investigative Site	Greensboro	North Carolina	United States	27405
39	Novartis Investigative Site	Akron	Ohio	United States	44320
40	Novartis Investigative Site	Columbus	Ohio	United States	43214
41	Novartis Investigative Site	Columbus	Ohio	United States	43221
42	Novartis Investigative Site	Westerville	Ohio	United States	43081
43	Novartis Investigative Site	Portland	Oregon	United States	97225
44	Novartis Investigative Site	Pittsburgh	Pennsylvania	United States	15212
45	Novartis Investigative Site	Willow Grove	Pennsylvania	United States	19090
46	Novartis Investigative Site	Greer	South Carolina	United States	29650
47	Novartis Investigative Site	Cordova	Tennessee	United States	38018
48	Novartis Investigative Site	Knoxville	Tennessee	United States	37922
49	Novartis Investigative Site	Nashville	Tennessee	United States	37205
50	Novartis Investigative Site	Greenville	Texas	United States	75401
51	Novartis Investigative Site	Lubbock	Texas	United States	79410
52	Novartis Investigative Site	Sherman	Texas	United States	75092
53	Novartis Investigative Site	Orem	Utah	United States	84058
54	Novartis Investigative Site	Salt Lake City	Utah	United States	84103
55	Novartis Investigative Site	Salt Lake City	Utah	United States	84132
56	Novartis Investigative Site	Kirkland	Washington	United States	98034
57	Novartis Investigative Site	Seattle	Washington	United States	98122
58	Novartis Investigative Site	Tacoma	Washington	United States	98405
59	Novartis Investigative Site	Waukesha	Wisconsin	United States	53188
60	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1428AQK
61	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000DSW
62	Novartis Investigative Site	Tucuman		Argentina	4000
63	Novartis Investigative Site	Liverpool	New South Wales	Australia	2170
64	Novartis Investigative Site	Vienna		Austria	1090
65	Novartis Investigative Site	Wien		Austria	1010
66	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
67	Novartis Investigative Site	Aalst		Belgium	9300
68	Novartis Investigative Site	Bruxelles		Belgium	1200
69	Novartis Investigative Site	Gent		Belgium	9000
70	Novartis Investigative Site	Sofia		Bulgaria	1113
71	Novartis Investigative Site	Sofia		Bulgaria	1413
72	Novartis Investigative Site	London	Ontario	Canada	N6A 5A5
73	Novartis Investigative Site	Ottawa	Ontario	Canada	K1H 8L6
74	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
75	Novartis Investigative Site	Greenfield Park	Quebec	Canada	J4V 2J2
76	Novartis Investigative Site	Osijek		Croatia	31000
77	Novartis Investigative Site	Zagreb		Croatia	10000
78	Novartis Investigative Site	Brno	Czech Republic	Czechia	656 91
79	Novartis Investigative Site	Havirov	Czech Republic	Czechia	736 01
80	Novartis Investigative Site	Teplice	Czech Republic	Czechia	415 01
81	Novartis Investigative Site	Ostrava-Poruba		Czechia	708 52
82	Novartis Investigative Site	Praha 10		Czechia	100 34
83	Novartis Investigative Site	Tampere		Finland	33100
84	Novartis Investigative Site	Turku		Finland	20520
85	Novartis Investigative Site	Nice	Cedex1	France	06001
86	Novartis Investigative Site	Bordeaux Cedex		France	33076
87	Novartis Investigative Site	Clermont-Ferrand		France	63000
88	Novartis Investigative Site	Montpellier		France	34295
89	Novartis Investigative Site	Paris Cedex 13		France	75651
90	Novartis Investigative Site	Rennes Cedex		France	35033
91	Novartis Investigative Site	Strasbourg		France	67098
92	Novartis Investigative Site	Bochum		Germany	44791
93	Novartis Investigative Site	Dresden		Germany	01307
94	Novartis Investigative Site	Essen		Germany	45147
95	Novartis Investigative Site	Hamburg		Germany	22179
96	Novartis Investigative Site	Hannover		Germany	30625
97	Novartis Investigative Site	Heidelberg		Germany	69120
98	Novartis Investigative Site	Homburg		Germany	66421
99	Novartis Investigative Site	Koln		Germany	50935
100	Novartis Investigative Site	Leipzig		Germany	04103
101	Novartis Investigative Site	Leipzig		Germany	04107
102	Novartis Investigative Site	Minden		Germany	32429
103	Novartis Investigative Site	Siegen		Germany	57076
104	Novartis Investigative Site	Ulm		Germany	89081
105	Novartis Investigative Site	Unterhaching		Germany	82008
106	Novartis Investigative Site	Budapest	HUN	Hungary	1204
107	Novartis Investigative Site	Esztergom	HUN	Hungary	2500
108	Novartis Investigative Site	Hyderabad	Andhra Pradesh	India	500018
109	Novartis Investigative Site	New Delhi	Delhi	India	110 060
110	Novartis Investigative Site	Mumbai	Maharashtra	India	400008
111	Novartis Investigative Site	Mumbai	Maharashtra	India	400012
112	Novartis Investigative Site	Pune	Maharashtra	India	411004
113	Novartis Investigative Site	Ludhiana	Punjab	India	141008
114	Novartis Investigative Site	Mumbai		India	400016
115	Novartis Investigative Site	Padova	PD	Italy	35128
116	Novartis Investigative Site	Roma	RM	Italy	00133
117	Novartis Investigative Site	Genova		Italy	16132
118	Novartis Investigative Site	Milano		Italy	20133
119	Novartis Investigative Site	Napoli		Italy	80138
120	Novartis Investigative Site	Rome		Italy	00178
121	Novartis Investigative Site	Riga	LV	Latvia	LV-1005
122	Novartis Investigative Site	Riga		Latvia	LV 1002
123	Novartis Investigative Site	Riga		Latvia	LV-1038
124	Novartis Investigative Site	Kaunas	LTU	Lithuania	LT 50161
125	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
126	Novartis Investigative Site	Chihuahua		Mexico	31238
127	Novartis Investigative Site	Drammen		Norway	1086
128	Novartis Investigative Site	Cercado De Lima	Lima	Peru	01
129	Novartis Investigative Site	San Isidro	Lima	Peru	27
130	Novartis Investigative Site	Lima		Peru	LIMA 13
131	Novartis Investigative Site	Glogow		Poland	36-060
132	Novartis Investigative Site	Rzeszow		Poland	35 055
133	Novartis Investigative Site	Warszawa		Poland	02 957
134	Novartis Investigative Site	Wroclaw		Poland	51-685
135	Novartis Investigative Site	Zabrze		Poland	41-800
136	Novartis Investigative Site	Matosinhos	Porto	Portugal	4454509
137	Novartis Investigative Site	Amadora		Portugal	2720-276
138	Novartis Investigative Site	Braga		Portugal	4710243
139	Novartis Investigative Site	Coimbra		Portugal	3000-075
140	Novartis Investigative Site	Lisboa		Portugal	1169-050
141	Novartis Investigative Site	Lisboa		Portugal	1500 650
142	Novartis Investigative Site	Lisboa		Portugal	1600190
143	Novartis Investigative Site	Loures		Portugal	2674514
144	Novartis Investigative Site	Porto		Portugal	4000001
145	Novartis Investigative Site	Santa Maria da Feira		Portugal	4520 211
146	Novartis Investigative Site	Ekaterinburg		Russian Federation	620109
147	Novartis Investigative Site	Kazan		Russian Federation	420021
148	Novartis Investigative Site	Krasnoyarsk		Russian Federation	660049
149	Novartis Investigative Site	Moscow		Russian Federation	127015
150	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603137
151	Novartis Investigative Site	Novosibirsk		Russian Federation	630087
152	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
153	Novartis Investigative Site	St. Petersburg		Russian Federation	197110
154	Novartis Investigative Site	St. Petersburg		Russian Federation	197376
155	Novartis Investigative Site	Bratislava		Slovakia	813 69
156	Novartis Investigative Site	Martin		Slovakia	036 59
157	Novartis Investigative Site	Ruzomberok		Slovakia	03426
158	Novartis Investigative Site	Pretoria		South Africa	0041
159	Novartis Investigative Site	Rosebank		South Africa	2196
160	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
161	Novartis Investigative Site	Sevilla	Andalucia	Spain	41017
162	Novartis Investigative Site	Pozuelo de Alarcon	Madrid	Spain	28223
163	Novartis Investigative Site	Baracaldo	Vizcaya	Spain	48903
164	Novartis Investigative Site	Madrid		Spain	28006
165	Novartis Investigative Site	Madrid		Spain	28034
166	Novartis Investigative Site	Madrid		Spain	28040
167	Novartis Investigative Site	Madrid		Spain	28222
168	Novartis Investigative Site	San Sebastian		Spain	20014
169	Novartis Investigative Site	Lugano		Switzerland	6900
170	Novartis Investigative Site	Tainan		Taiwan	70403
171	Novartis Investigative Site	Haseki / Istanbul		Turkey	34096
172	Novartis Investigative Site	Izmir		Turkey	35340
173	Novartis Investigative Site	Mersin		Turkey	33079
174	Novartis Investigative Site	Trabzon		Turkey	61080
175	Novartis Investigative Site	Luton	Beds	United Kingdom	LU4 0DZ
176	Novartis Investigative Site	Sheffield	South Yorkshire	United Kingdom	S10 2JF
177	Novartis Investigative Site	London		United Kingdom	SE5 9RS
178	Novartis Investigative Site	London		United Kingdom	SW17 0QT

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis

Study Documents (Full-Text)

• Study Protocol - Aug 6, 2018
• Statistical Analysis Plan - Oct 17, 2019

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02792231
• Other Study ID Numbers: COMB157G2302; 2015-005419-33
• First Posted: Jun 7, 2016
• Last Update Posted: Nov 22, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Relapsing multiple sclerosis; Ofatumumab; adult; OMB157; multiple sclerosis; T1 lesions; T2 lesions; relapse; GD-enhancing MRI; McDonald criteria; RRMS; SPMS
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Teriflunomide; Ofatumumab; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	A total of 1280 patients were screened, of whom 955 patients were randomized into the study.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Period Title: Overall Study
STARTED	481	474
COMPLETED	399	390
NOT COMPLETED	82	84

Baseline Characteristics

Arm/Group Title	OMB 20 mg	TER 14 mg	Total
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)	Total of all reporting groups
Overall Participants	481	474	955
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.0 (9.28)	38.2 (9.47)	38.1 (9.37)
Sex: Female, Male (Count of Participants)
Female	319 66.3%	319 67.3%	638 66.8%
Male	162 33.7%	155 32.7%	317 33.2%
Race/Ethnicity, Customized (Count of Participants)
Asian	21 4.4%	19 4%	40 4.2%
Black or African American	13 2.7%	18 3.8%	31 3.2%
White	418 86.9%	417 88%	835 87.4%
Other	20 4.2%	14 3%	34 3.6%
Unknown	9 1.9%	6 1.3%	15 1.6%
Number of relapses in the past 12 months prior to screening (Number of relapses) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of relapses]	1.3 (0.74)	1.3 (0.73)	1.3 (0.74)
Expanded Disability Status Scale (EDSS) (Score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a scale]	2.90 (1.343)	2.86 (1.373)	2.88 (1.358)
Number of gadolinium-enhancing T1 lesions (T1 lesions) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T1 lesions]	1.6 (4.07)	1.5 (4.07)	1.5 (4.07)

Outcome Measures

1. Primary Outcome

Title	Annualized Relapse Rate (ARR)
Description	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).
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	469	470
Mean (95% Confidence Interval) [number of relapses in a year]	0.10	0.25

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Obtained from fitting a negative binomial regression model with log-link to the number of relapses, adjusted for treatment and region as factors, number of relapses in previous year, baseline EDSS, baseline number of Gd-enhancing lesions and the patient's age at baseline as covariates. The natural log of the time-in-study was used as offset to annualize the relapse rate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.416
	Confidence Interval	(2-Sided) 95%; 0.309 to 0.560
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	944	932
Month 18 - from Kaplan Meier estimates	9.4 2%	13.5 2.8%
Month 24 - from Kaplan Meier estimates	10.9 2.3%	15.0 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Pooled data - 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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.657
	Confidence Interval	(2-Sided) 95%; 0.500 to 0.863
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	479	473
Month 18 - from Kaplan Meier estimates	9.3 1.9%	13.2 2.8%
Month 24 - from Kaplan Meier estimates	10.5 2.2%	14.6 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.662
	Confidence Interval	(2-Sided) 95%; 0.449 to 0.977
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	944	932
Month 18- from Kaplan Meier estimates	7.8 1.6%	10.7 2.3%
Month 24 - from Kaplan Meier estimates	8.1 1.7%	12.0 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.676
	Confidence Interval	(2-Sided) 95%; 0.498 to 0.917
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	479	473
Month 18- from Kaplan Meier estimates	8.0 1.7%	10.0 2.1%
Month 24 - from Kaplan Meier estimates	8.0 1.7%	10.9 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.759
	Confidence Interval	(2-Sided) 95%; 0.490 to 1.174
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	749	724
Month 18 - from Kaplan Meier estimates	10.1 2.1%	7.6 1.6%
Month 24 - from Kaplan Meier estimates	11.0 2.3%	8.2 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.092
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.355
	Confidence Interval	(2-Sided) 95%; 0.952 to 1.928
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	374	361
Month 18 - from Kaplan Meier estimates	11.1 2.3%	8.1 1.7%
Month 24 - from Kaplan Meier estimates	12.3 2.6%	8.1 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.090
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.523
	Confidence Interval	(2-Sided) 95%; 0.936 to 2.477
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Gadolinium-enhancing T1 Lesions Per MRI Scan
Description	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.
Time Frame	Baseline, yearly up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	438	433
Mean (95% Confidence Interval) [lesions per scan]	0.0317	0.5172

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.101
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate)
Description	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
Time Frame	Baseline, yearly up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	448	442
Month 12 n=422,410	0.94	4.41
Month 24 n=90,76	0.72	3.72
EOS n=448,442	0.64	4.16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Month 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Month 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.12 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	End of Study
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Neurofilament Light Chain (NfL) Concentration in Serum
Description	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.
Time Frame	Month 3, 12 and 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	425	423
Month 3 n=425,423	8.92	10.02
Month 12 n=406,406	7.06	9.53
Month 24 n=345,349	6.80	8.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Month 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models for Repeated Measures (MMRM)
Method of Estimation	Estimation Parameter	Geo-mean ratio
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.85 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Month 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models for Repeated Measures (MMRM)
Method of Estimation	Estimation Parameter	Geo-mean ratio
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.70 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	Month 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models for Repeated Measures (MMRM)
Method of Estimation	Estimation Parameter	Geo-mean ratio
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.71 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline
Description	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
Time Frame	Baseline, Months 12 and 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	437	433
Mean (95% Confidence Interval) [percentage of brain volume loss]	-0.29	-0.35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.128
	Comments
	Method	random coefficient model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Participants With Confirmed Relapse
Description	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).
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	469	470
Number (95% Confidence Interval) [percentage of participants]	16.51 3.4%	32.68 6.9%

13. Secondary Outcome

Title	Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment
Description	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).
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	461	467
Mean (95% Confidence Interval) [number of relapses in a year]	0.096	0.241

14. Secondary Outcome

Title	3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data
Description	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.
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	944	932
Month 18 - from Kaplan Meier estimates	9.4 2%	13.5 2.8%
Month 24 - from Kaplan Meier estimates	10.9 2.3%	15.0 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.641
	Confidence Interval	(2-Sided) 95%; 0.486 to 0.847
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data
Description	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.
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	944	932
Month 18- from Kaplan Meier estimates	7.8 1.6%	10.7 2.3%
Month 24 - from Kaplan Meier estimates	8.1 1.7%	12.0 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OMB 20 mg, TER 14 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.657
	Confidence Interval	(2-Sided) 95%; 0.481 to 0.898
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data
Description	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
Time Frame	Baseline, every 6 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	930	917
Month 18 - from Kaplan Meier estimates	14.3 3%	13.7 2.9%
Month 24 - from Kaplan Meier estimates	15.4 3.2%	14.0 3%

17. Secondary Outcome

Title	6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data
Description	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.
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	941	930
Month 18 - from Kaplan Meier estimates	20.5 4.3%	21.7 4.6%
Month 24 - from Kaplan Meier estimates	21.4 4.4%	22.6 4.8%

18. Secondary Outcome

Title	Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data
Description	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.
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	921	909
Month 6 n=921,909	1.02	0.64
Month 12 n=879,863	1.82	1.70
Month 18 n=849,808	2.84	2.05
Month 24 n=492,468	3.50	2.39
Month 30 n=156,117	3.53	2.97

19. Secondary Outcome

Title	6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	936	925
Month 18 - from Kaplan Meier estimates	11.0 2.3%	10.4 2.2%
Month 24 - from Kaplan Meier estimates	11.4 2.4%	10.6 2.2%

20. Secondary Outcome

Title	6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data
Description	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.
Time Frame	Baseline, every 6 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	932	920
Month 18 - from Kaplan Meier estimates	2.9 0.6%	3.3 0.7%
Month 24 - from Kaplan Meier estimates	2.9 0.6%	3.3 0.7%

21. Secondary Outcome

Title	6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data
Description	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.
Time Frame	Baseline, every 3 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set from combined studies.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	749	724
Month 18 - from Kaplan Meier estimates	5.4 1.1%	4.6 1%
Month 24 - from Kaplan Meier estimates	5.8 1.2%	4.6 1%

22. Secondary Outcome

Title	Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS)
Description	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.
Time Frame	Month 12 up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	369	348
Mean (95% Confidence Interval) [T2 lesions per year]	0.13	3.84

23. Secondary Outcome

Title	Percent Change in T2 Lesion Volume Relative to Baseline
Description	Percent change from baseline in total T2 lesion volume
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	447	437
Month 12 n=447,437	-2.4 (8.66)	10.1 (38.57)
Month 24 n=330,320	-2.6 (9.34)	17.8 (53.48)

24. Secondary Outcome

Title	No Evidence of Disease Activity (NEDA-4)
Description	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%.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	433	427
Month 12 n=433,427	23.8 4.9%	17.8 3.8%
Month 24 n=92,78	9.8 2%	5.1 1.1%

25. Secondary Outcome

Title	Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline
Description	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.
Time Frame	Baseline, every 6 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	473	461
Month 6 n=473,461	-2.20 (0.652)	-0.46 (0.659)
Month 12 n=448,438	-2.47 (0.698)	-0.49 (0.704)
Month 18 n=425,409	-2.29 (0.784)	1.53 (0.794)
Month 24 n=235,238	-2.93 (0.904)	0.62 (0.905)
Month 30 n=70,54	-2.49 (1.270)	1.44 (1.397)

26. Secondary Outcome

Title	Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline
Description	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.
Time Frame	Baseline, every 6 months up to 2.5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	473	461
Month 6 n=473,461	-5.96 (0.807)	-3.77 (0.816)
Month 12 n=448,436	-5.42 (0.830)	-3.88 (0.839)
Month 18 n=423,409	-6.23 (0.884)	-2.51 (0.896)
Month 24 n=234,238	-6.10 (1.092)	-3.12 (1.090)
Month 30 n=70,54	-6.25 (1.623)	-4.75 (1.797)

27. Secondary Outcome

Title	Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data
Description	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).
Time Frame	Baseline up to 2.5 years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	871	841
High > median n=443,410	0.08	0.21
Low <= median n=428,431	0.12	0.23

28. Secondary Outcome

Title	Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data
Description	Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate).
Time Frame	Baseline, yearly up to 2.5 years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	850	823
High > median n=432,402	0.95	5.28
Low <= median n=418,421	0.39	3.02

29. Secondary Outcome

Title	Brain Volume Loss by NfL High-low Subgroups - Pooled Data
Description	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.
Time Frame	Baseline, Months 12 and 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	OMB 20 mg	TER 14 mg
Arm/Group Description	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)	Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
Measure Participants	819	794
High > median n=416,387	-0.32	-0.43
Low <= median n=403,407	-0.24	-0.29

30. Secondary Outcome

Title	Pharmacokinetic (PK) Concentrations of Ofatumumab
Description	Summary statistics of pharmacokinetic (PK) concentrations from trough samples collected within a 7-day window prior or at day of dosing.
Time Frame	Baseline, Weeks 4, 12, 24, 48, 96

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	OMB 20 mg
Arm/Group Description	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)
Measure Participants	481
Baseline n=325	0.00325 (0.031372)
Week 4 n=346	1.26512 (0.964645)
Week 12 n=257	0.20932 (0.287839)
Week 24 n=243	0.38203 (0.433175)
Week 48 n=240	0.59087 (0.594490)
Week 96 n=304	1.13218 (0.991141)

Adverse Events

Time Frame	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
Arm/Group Title	OMB 20mg		TER 14mg
Arm/Group Description	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)		Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
All Cause Mortality
	OMB 20mg		TER 14mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/481 (0%)		1/474 (0.2%)
Serious Adverse Events
	OMB 20mg		TER 14mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/481 (8.7%)		37/474 (7.8%)
Cardiac disorders
Bundle branch block bilateral	1/481 (0.2%)		0/474 (0%)
Coronary artery disease	0/481 (0%)		1/474 (0.2%)
Myocardial infarction	1/481 (0.2%)		0/474 (0%)
Nodal arrhythmia	1/481 (0.2%)		0/474 (0%)
Bundle branch block bilateral	1/481 (0.2%)		0/474 (0%)
Coronary artery disease	0/481 (0%)		1/474 (0.2%)
Myocardial infarction	1/481 (0.2%)		0/474 (0%)
Nodal arrhythmia	1/481 (0.2%)		0/474 (0%)
Eye disorders
Diplopia	0/481 (0%)		1/474 (0.2%)
Diplopia	0/481 (0%)		1/474 (0.2%)
Gastrointestinal disorders
Abdominal pain upper	1/481 (0.2%)		0/474 (0%)
Enteritis	1/481 (0.2%)		0/474 (0%)
Intestinal obstruction	0/481 (0%)		1/474 (0.2%)
Pancreatitis acute	1/481 (0.2%)		0/474 (0%)
Umbilical hernia	1/481 (0.2%)		0/474 (0%)
Abdominal pain upper	1/481 (0.2%)		0/474 (0%)
Enteritis	1/481 (0.2%)		0/474 (0%)
Intestinal obstruction	0/481 (0%)		1/474 (0.2%)
Pancreatitis acute	1/481 (0.2%)		0/474 (0%)
Umbilical hernia	1/481 (0.2%)		0/474 (0%)
General disorders
Drug withdrawal syndrome	1/481 (0.2%)		0/474 (0%)
Non-cardiac chest pain	0/481 (0%)		1/474 (0.2%)
Pyrexia	1/481 (0.2%)		0/474 (0%)
Drug withdrawal syndrome	1/481 (0.2%)		0/474 (0%)
Non-cardiac chest pain	0/481 (0%)		1/474 (0.2%)
Pyrexia	1/481 (0.2%)		0/474 (0%)
Hepatobiliary disorders
Cholecystitis	0/481 (0%)		1/474 (0.2%)
Cholelithiasis	2/481 (0.4%)		0/474 (0%)
Hepatic failure	0/481 (0%)		1/474 (0.2%)
Cholecystitis	0/481 (0%)		1/474 (0.2%)
Cholecystitis acute	1/481 (0.2%)		0/474 (0%)
Cholelithiasis	2/481 (0.4%)		0/474 (0%)
Hepatic failure	0/481 (0%)		1/474 (0.2%)
Infections and infestations
Appendicitis	5/481 (1%)		1/474 (0.2%)
Cystitis	0/481 (0%)		1/474 (0.2%)
Gastroenteritis	1/481 (0.2%)		0/474 (0%)
Influenza	1/481 (0.2%)		0/474 (0%)
Lower respiratory tract infection	1/481 (0.2%)		0/474 (0%)
Osteomyelitis	0/481 (0%)		1/474 (0.2%)
Paronychia	0/481 (0%)		1/474 (0.2%)
Peritonitis	0/481 (0%)		1/474 (0.2%)
Pneumonia	1/481 (0.2%)		0/474 (0%)
Postoperative abscess	0/481 (0%)		1/474 (0.2%)
Respiratory tract infection viral	1/481 (0.2%)		0/474 (0%)
Sepsis	0/481 (0%)		1/474 (0.2%)
Urinary tract infection	2/481 (0.4%)		2/474 (0.4%)
Urosepsis	1/481 (0.2%)		0/474 (0%)
Viral infection	0/481 (0%)		1/474 (0.2%)
Appendicitis	5/481 (1%)		1/474 (0.2%)
Cystitis	0/481 (0%)		1/474 (0.2%)
Gastroenteritis	1/481 (0.2%)		0/474 (0%)
Influenza	1/481 (0.2%)		0/474 (0%)
Lower respiratory tract infection	1/481 (0.2%)		0/474 (0%)
Osteomyelitis	0/481 (0%)		1/474 (0.2%)
Paronychia	0/481 (0%)		1/474 (0.2%)
Peritonitis	0/481 (0%)		1/474 (0.2%)
Pneumonia	1/481 (0.2%)		0/474 (0%)
Postoperative abscess	0/481 (0%)		1/474 (0.2%)
Respiratory tract infection viral	1/481 (0.2%)		0/474 (0%)
Sepsis	0/481 (0%)		1/474 (0.2%)
Urinary tract infection	2/481 (0.4%)		2/474 (0.4%)
Urosepsis	1/481 (0.2%)		0/474 (0%)
Viral infection	0/481 (0%)		1/474 (0.2%)
Injury, poisoning and procedural complications
Ankle fracture	2/481 (0.4%)		0/474 (0%)
Bone contusion	0/481 (0%)		1/474 (0.2%)
Concussion	1/481 (0.2%)		0/474 (0%)
Craniocerebral injury	0/481 (0%)		1/474 (0.2%)
Fall	1/481 (0.2%)		1/474 (0.2%)
Femoral neck fracture	0/481 (0%)		1/474 (0.2%)
Head injury	0/481 (0%)		1/474 (0.2%)
Humerus fracture	1/481 (0.2%)		0/474 (0%)
Incisional hernia	0/481 (0%)		1/474 (0.2%)
Joint dislocation	1/481 (0.2%)		0/474 (0%)
Ligament sprain	0/481 (0%)		1/474 (0.2%)
Post procedural haematoma	0/481 (0%)		1/474 (0.2%)
Post procedural inflammation	0/481 (0%)		1/474 (0.2%)
Radius fracture	0/481 (0%)		1/474 (0.2%)
Rib fracture	1/481 (0.2%)		0/474 (0%)
Road traffic accident	1/481 (0.2%)		0/474 (0%)
Tendon injury	1/481 (0.2%)		0/474 (0%)
Upper limb fracture	1/481 (0.2%)		0/474 (0%)
Ankle fracture	2/481 (0.4%)		0/474 (0%)
Bone contusion	0/481 (0%)		1/474 (0.2%)
Concussion	1/481 (0.2%)		0/474 (0%)
Craniocerebral injury	0/481 (0%)		1/474 (0.2%)
Fall	1/481 (0.2%)		1/474 (0.2%)
Femoral neck fracture	0/481 (0%)		1/474 (0.2%)
Head injury	0/481 (0%)		1/474 (0.2%)
Humerus fracture	1/481 (0.2%)		0/474 (0%)
Incisional hernia	0/481 (0%)		1/474 (0.2%)
Joint dislocation	1/481 (0.2%)		0/474 (0%)
Ligament sprain	0/481 (0%)		1/474 (0.2%)
Post procedural haematoma	0/481 (0%)		1/474 (0.2%)
Post procedural inflammation	0/481 (0%)		1/474 (0.2%)
Radius fracture	0/481 (0%)		1/474 (0.2%)
Rib fracture	1/481 (0.2%)		0/474 (0%)
Road traffic accident	1/481 (0.2%)		0/474 (0%)
Tendon injury	1/481 (0.2%)		0/474 (0%)
Upper limb fracture	1/481 (0.2%)		0/474 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc compression	1/481 (0.2%)		0/474 (0%)
Intervertebral disc protrusion	1/481 (0.2%)		1/474 (0.2%)
Neck pain	1/481 (0.2%)		0/474 (0%)
Pathological fracture	0/481 (0%)		1/474 (0.2%)
Spondylitis	1/481 (0.2%)		0/474 (0%)
Intervertebral disc compression	1/481 (0.2%)		0/474 (0%)
Intervertebral disc protrusion	1/481 (0.2%)		1/474 (0.2%)
Neck pain	1/481 (0.2%)		0/474 (0%)
Pathological fracture	0/481 (0%)		1/474 (0.2%)
Spondylitis	1/481 (0.2%)		0/474 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	2/481 (0.4%)		1/474 (0.2%)
Fibroadenoma of breast	1/481 (0.2%)		0/474 (0%)
Uterine leiomyoma	2/481 (0.4%)		1/474 (0.2%)
Basal cell carcinoma	2/481 (0.4%)		1/474 (0.2%)
Benign breast neoplasm	1/481 (0.2%)		0/474 (0%)
Fibroadenoma of breast	1/481 (0.2%)		0/474 (0%)
Uterine leiomyoma	2/481 (0.4%)		1/474 (0.2%)
Nervous system disorders
Headache	1/481 (0.2%)		0/474 (0%)
Lumbar radiculopathy	0/481 (0%)		1/474 (0.2%)
Multiple sclerosis	0/481 (0%)		1/474 (0.2%)
Multiple sclerosis relapse	0/481 (0%)		1/474 (0.2%)
Myelopathy	0/481 (0%)		1/474 (0.2%)
Quadriplegia	1/481 (0.2%)		0/474 (0%)
Syncope	2/481 (0.4%)		0/474 (0%)
Trigeminal neuralgia	1/481 (0.2%)		0/474 (0%)
Headache	2/481 (0.4%)		0/474 (0%)
Lumbar radiculopathy	0/481 (0%)		1/474 (0.2%)
Multiple sclerosis	0/481 (0%)		1/474 (0.2%)
Multiple sclerosis relapse	1/481 (0.2%)		1/474 (0.2%)
Myelopathy	0/481 (0%)		1/474 (0.2%)
Quadriparesis	1/481 (0.2%)		0/474 (0%)
Syncope	2/481 (0.4%)		0/474 (0%)
Trigeminal neuralgia	1/481 (0.2%)		0/474 (0%)
Psychiatric disorders
Anxiety	0/481 (0%)		1/474 (0.2%)
Depression	0/481 (0%)		1/474 (0.2%)
Major depression	0/481 (0%)		1/474 (0.2%)
Suicidal ideation	1/481 (0.2%)		0/474 (0%)
Suicide attempt	0/481 (0%)		1/474 (0.2%)
Anxiety	0/481 (0%)		1/474 (0.2%)
Depression	0/481 (0%)		1/474 (0.2%)
Major depression	0/481 (0%)		1/474 (0.2%)
Suicidal ideation	1/481 (0.2%)		0/474 (0%)
Suicide attempt	0/481 (0%)		1/474 (0.2%)
Renal and urinary disorders
Urinary retention	0/481 (0%)		1/474 (0.2%)
Urinary retention	0/481 (0%)		1/474 (0.2%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/481 (0%)		1/474 (0.2%)
Testicular infarction	1/481 (0.2%)		0/474 (0%)
Uterine haemorrhage	0/481 (0%)		1/474 (0.2%)
Uterine polyp	0/481 (0%)		2/474 (0.4%)
Uterovaginal prolapse	0/481 (0%)		1/474 (0.2%)
Benign prostatic hyperplasia	0/481 (0%)		1/474 (0.2%)
Testicular infarction	1/481 (0.2%)		0/474 (0%)
Uterine haemorrhage	0/481 (0%)		1/474 (0.2%)
Uterine polyp	0/481 (0%)		2/474 (0.4%)
Uterovaginal prolapse	0/481 (0%)		1/474 (0.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/481 (0%)		1/474 (0.2%)
Pulmonary sarcoidosis	1/481 (0.2%)		0/474 (0%)
Pulmonary embolism	0/481 (0%)		1/474 (0.2%)
Pulmonary sarcoidosis	1/481 (0.2%)		0/474 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/481 (0.2%)		0/474 (0%)
Angioedema	1/481 (0.2%)		0/474 (0%)
Lichen sclerosus	0/481 (0%)		1/474 (0.2%)
Vascular disorders
Aortic dissection	0/481 (0%)		1/474 (0.2%)
Deep vein thrombosis	0/481 (0%)		1/474 (0.2%)
Aortic dissection	0/481 (0%)		1/474 (0.2%)
Deep vein thrombosis	1/481 (0.2%)		1/474 (0.2%)
Other (Not Including Serious) Adverse Events
	OMB 20mg		TER 14mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	348/481 (72.3%)		322/474 (67.9%)
Gastrointestinal disorders
Diarrhoea	28/481 (5.8%)		49/474 (10.3%)
Nausea	30/481 (6.2%)		32/474 (6.8%)
Diarrhoea	28/481 (5.8%)		49/474 (10.3%)
Nausea	30/481 (6.2%)		32/474 (6.8%)
General disorders
Fatigue	25/481 (5.2%)		32/474 (6.8%)
Injection site reaction	61/481 (12.7%)		26/474 (5.5%)
Fatigue	25/481 (5.2%)		32/474 (6.8%)
Injection site reaction	61/481 (12.7%)		26/474 (5.5%)
Infections and infestations
Influenza	30/481 (6.2%)		30/474 (6.3%)
Nasopharyngitis	88/481 (18.3%)		87/474 (18.4%)
Upper respiratory tract infection	49/481 (10.2%)		47/474 (9.9%)
Urinary tract infection	54/481 (11.2%)		35/474 (7.4%)
Influenza	27/481 (5.6%)		28/474 (5.9%)
Nasopharyngitis	88/481 (18.3%)		88/474 (18.6%)
Upper respiratory tract infection	52/481 (10.8%)		47/474 (9.9%)
Urinary tract infection	55/481 (11.4%)		34/474 (7.2%)
Injury, poisoning and procedural complications
Injection related reaction	119/481 (24.7%)		66/474 (13.9%)
Injection related reaction	119/481 (24.7%)		66/474 (13.9%)
Investigations
Blood immunoglobulin M decreased	30/481 (6.2%)		8/474 (1.7%)
Blood immunoglobulin M decreased	31/481 (6.4%)		8/474 (1.7%)
Musculoskeletal and connective tissue disorders
Back pain	35/481 (7.3%)		24/474 (5.1%)
Pain in extremity	23/481 (4.8%)		30/474 (6.3%)
Arthralgia	30/481 (6.2%)		25/474 (5.3%)
Back pain	35/481 (7.3%)		24/474 (5.1%)
Pain in extremity	22/481 (4.6%)		30/474 (6.3%)
Nervous system disorders
Headache	68/481 (14.1%)		65/474 (13.7%)
Headache	69/481 (14.3%)		66/474 (13.9%)
Psychiatric disorders
Anxiety	28/481 (5.8%)		17/474 (3.6%)
Depression	24/481 (5%)		24/474 (5.1%)
Anxiety	30/481 (6.2%)		17/474 (3.6%)
Depression	23/481 (4.8%)		24/474 (5.1%)
Respiratory, thoracic and mediastinal disorders
Cough	17/481 (3.5%)		24/474 (5.1%)
Skin and subcutaneous tissue disorders
Alopecia	27/481 (5.6%)		74/474 (15.6%)
Alopecia	27/481 (5.6%)		75/474 (15.8%)
Vascular disorders
Hypertension	20/481 (4.2%)		31/474 (6.5%)
Hypertension	20/481 (4.2%)		32/474 (6.8%)

Limitations/Caveats

This study was not powered for the analysis of some secondary endpoints as a stand-alone study. It was pre-specified in the study protocol to combine the data with study COMB157G2301 to address these endpoints.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.