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    Clinical Trial Results:
    A randomized, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of ofatumumab versus teriflunomide in patients with relapsing multiple sclerosis

    Summary
    EudraCT number
    		 2015-005419-33
    Trial protocol
    		 DE   HU   BE   FI   GB   AT   CZ   PT   SK   ES   LV   LT   BG   FR   HR   IT  
    Global end of trial date
    22 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Nov 2021
    First version publication date
    06 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    COMB157G2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02792231
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstrate that ofatumumab 20 mg s.c. once every 4 weeks is superior to teriflunomide 14 mg p.o. once daily in reducing the frequency of confirmed relapses as evaluated by the annualized relapse rate (ARR) in patients with relapsing multiple sclerosis (RMS).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Croatia: 61
    Country: Number of subjects enrolled
    Czechia: 42
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    India: 31
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Latvia: 15
    Country: Number of subjects enrolled
    Lithuania: 21
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Poland: 46
    Country: Number of subjects enrolled
    Portugal: 36
    Country: Number of subjects enrolled
    Russian Federation: 199
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    United States: 200
    Worldwide total number of subjects
    955
    EEA total number of subjects
    435
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    955
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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 and Baseline Characteristics for participants from other study.

    Pre-assignment
    Screening details
    		 A total of 1280 patients were screened, of whom 955 patients were randomized into the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OMB 20 mg
    Arm 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)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo matching teriflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide-matching placebo capsule orally once daily

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Ofatumumab 20 mg pre-filled syringes for subcutaneous injection on Days 1 ,7,14, Week 4 and every 4 weeks thereafter

    Arm title
    		 TER 14 mg
    Arm description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg capsule orally once daily

    Investigational medicinal product name
    Placebo matching ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Ofatumumab-matching placebo subcutaneous injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter

    Number of subjects in period 1
    		OMB 20 mg TER 14 mg
    Started
    481
    474
    Completed
    399
    390
    Not completed
    82
    84
         Physician decision
    14
    12
         Adverse event, non-fatal
    15
    11
         Technical problems
    -
    1
         Non-compliance with study treatment
    2
    1
         Protocol deviation
    2
    -
         Pregnancy
    1
    3
         Patient/guardian decision
    32
    42
         Lost to follow-up
    9
    5
         Lack of efficacy
    7
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OMB 20 mg
    Reporting 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)

    Reporting group title
    TER 14 mg
    Reporting group description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)

    Reporting group values
    		 OMB 20 mg TER 14 mg Total
    Number of subjects
    		 481 474 955
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 481 474 955
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 38.0 ± 9.28 38.2 ± 9.47 -
    Sex: Female, Male
    Units: Participants
        Female
    		 319 319 638
        Male
    		 162 155 317
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 21 19 40
        Black or African American
    		 13 18 31
        White
    		 418 417 835
        Other
    		 20 14 34
        Unknown
    		 9 6 15
    Number of relapses in the past 12 months prior to screening
    Reported numbers are from investigator records
    Units: Number of relapses
        arithmetic mean (standard deviation)
    		 1.3 ± 0.74 1.3 ± 0.73 -
    Expanded Disability Status Scale (EDSS)
    The EDSS uses an ordinal scale to assess neurologic impairment in MS based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar,Sensory, Bowel & Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS).
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 2.90 ± 1.343 2.86 ± 1.373 -
    Number of Gd-enhancing T1 lesions
    Magnetic Resonance Imaging (MRI) scans of the brain were were read by the central MRI reading center. The central reading center was blinded with no access to information on treatment assignments
    Units: T1 lesions
        arithmetic mean (standard deviation)
    		 1.6 ± 4.07 1.5 ± 4.07 -

    End points

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    End points reporting groups
    Reporting group title
    OMB 20 mg
    Reporting 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)

    Reporting group title
    TER 14 mg
    Reporting group description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)

    Subject analysis set title
    OMB 20 mg - Pooled
    Subject analysis set type
    		 Full analysis
    Subject analysis set 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). Full analysis set from combined studies.

    Subject analysis set title
    TER 14 mg - Pooled
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter). Full analysis set from combined studies.

    Primary: Annualized relapse rate (ARR)

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    End point title
    		 Annualized relapse rate (ARR)
    End point 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).
    End point type
    Primary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    469
    470
    Units: number of relapses in a year
        arithmetic mean (confidence interval 95%)
    0.10 (0.08 to 0.13)
    0.25 (0.21 to 0.30)
    Statistical analysis title
    		 ARR
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    939
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.416
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.309
         upper limit
    		 0.56

    Secondary: 3-month confirmed disability worsening (3mCDW) based on EDSS - Pooled Data

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    End point title
    		 3-month confirmed disability worsening (3mCDW) based on EDSS - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    944
    932
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    9.4 (7.6 to 11.5)
    13.5 (11.4 to 16.0)
        Month 24 - from Kaplan Meier estimates
    10.9 (8.8 to 13.4)
    15.0 (12.6 to 17.7)
    Statistical analysis title
    		 3mCDW - pooled
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg - Pooled v TER 14 mg - Pooled
    Number of subjects included in analysis
    1876
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.003
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.863

    Secondary: 3-month confirmed disability worsening (3mCDW) based on EDSS - Study COMB157G2302

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    End point title
    		 3-month confirmed disability worsening (3mCDW) based on EDSS - Study COMB157G2302
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    479
    473
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    9.3 (6.9 to 12.5)
    13.2 (10.3 to 16.7)
        Month 24 - from Kaplan Meier estimates
    10.5 (7.8 to 14.1)
    14.6 (11.5 to 18.6)
    Statistical analysis title
    		 3mCDW - pooled
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.038
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.662
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.449
         upper limit
    		 0.977

    Secondary: 6-month confirmed disability worsening (6mCDW) based on EDSS - Pooled Data

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    End point title
    		 6-month confirmed disability worsening (6mCDW) based on EDSS - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    944
    932
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18- from Kaplan Meier estimates
    7.8 (6.2 to 9.7)
    10.7 (8.9 to 13.0)
        Month 24 - from Kaplan Meier estimates
    8.1 (6.5 to 10.2)
    12.0 (9.9 to 14.5)
    Statistical analysis title
    		 6mCDW - pooled
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg - Pooled v TER 14 mg - Pooled
    Number of subjects included in analysis
    1876
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.012
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.676
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.498
         upper limit
    		 0.917

    Secondary: 6-month confirmed disability worsening (6mCDW) based on EDSS - Study COMB157G2302

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    End point title
    		 6-month confirmed disability worsening (6mCDW) based on EDSS - Study COMB157G2302
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    479
    473
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18- from Kaplan Meier estimates
    8.0 (5.9 to 11.0)
    10.0 (7.5 to 13.2)
        Month 24 - from Kaplan Meier estimates
    8.0 (5.9 to 11.0)
    10.9 (8.2 to 14.4)
    Statistical analysis title
    		 6mCDW - pooled
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.215
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.759
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.174

    Secondary: 6-month confirmed disability improvement (6mCDI ) based on EDSS - Pooled Data

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    End point title
    		 6-month confirmed disability improvement (6mCDI ) based on EDSS - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    749
    724
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    10.1 (8.1 to 12.6)
    7.6 (5.8 to 9.8)
        Month 24 - from Kaplan Meier estimates
    11.0 (8.8 to 13.7)
    8.2 (6.3 to 10.6)
    Statistical analysis title
    		 6mCDI - pooled
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg - Pooled v TER 14 mg - Pooled
    Number of subjects included in analysis
    1473
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.092
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.355
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.952
         upper limit
    		 1.928

    Secondary: 6-month confirmed disability improvement (6mCDI ) based on EDSS - Study COMB157G2302

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    End point title
    		 6-month confirmed disability improvement (6mCDI ) based on EDSS - Study COMB157G2302
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    374
    361
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    11.1 (8.2 to 14.8)
    8.1 (5.6 to 11.6)
        Month 24 - from Kaplan Meier estimates
    12.3 (9.1 to 16.5)
    8.1 (5.6 to 11.6)
    Statistical analysis title
    		 6mCDI
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    735
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.09
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.523
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.936
         upper limit
    		 2.477

    Secondary: Number of gadolinium-enhancing T1 lesions per MRI scan

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    End point title
    		 Number of gadolinium-enhancing T1 lesions per MRI scan
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, yearly up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    438
    433
    Units: lesions per scan
        arithmetic mean (confidence interval 95%)
    0.0317 (0.021 to 0.048)
    0.5172 (0.404 to 0.662)
    Statistical analysis title
    		 Gd + T1 Lesions
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    871
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.037
         upper limit
    		 0.101

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

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    End point title
    		 Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate)
    End point 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
    End point type
    Secondary
    End point timeframe
    Baseline, yearly up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    448
    442
    Units: T2 lesions per year
    arithmetic mean (confidence interval 95%)
        Month 12 n=422,410
    0.94 (0.80 to 1.11)
    4.41 (3.83 to 5.08)
        Month 24 n=90,76
    0.72 (0.51 to 1.02)
    3.72 (2.68 to 5.18)
        EOS n=448,442
    0.64 (0.55 to 0.75)
    4.16 (3.64 to 4.75)
    Statistical analysis title
    		 T2 Lesions Month 12
    Statistical analysis description
    Month 12
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    890
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.27
    Statistical analysis title
    		 T2 Lesions End of Study
    Statistical analysis description
    End of Study
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    890
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.19
    Statistical analysis title
    		 T2 Lesions Month 24
    Statistical analysis description
    Month 24
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    890
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.31

    Secondary: Neurofilament light chain (NfL) concentration in serum

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    End point title
    		 Neurofilament light chain (NfL) concentration in serum
    End point 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.
    End point type
    Secondary
    End point timeframe
    Month 3, 12 and 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    425
    423
    Units: pg/mL
    geometric mean (confidence interval 95%)
        Month 3 n=425,423
    8.92 (8.62 to 9.23)
    10.02 (9.68 to 10.36)
        Month 12 n=406,406
    7.06 (6.77 to 7.37)
    9.53 (9.13 to 9.95)
        Month 24 n=345,349
    6.80 (6.47 to 7.13)
    8.99 (8.57 to 9.44)
    Statistical analysis title
    		 NfL Month 3
    Statistical analysis description
    Month 3
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    848
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geo-mean ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 0.93
    Statistical analysis title
    		 NfL Month 12
    Statistical analysis description
    Month 12
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    848
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geo-mean ratio
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.79
    Statistical analysis title
    		 NfL Month 24
    Statistical analysis description
    Month 24
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    848
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geo-mean ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.81

    Secondary: Annualized rate of brain volume loss based on assessments of percent brain volume change from baseline

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    End point title
    		 Annualized rate of brain volume loss based on assessments of percent brain volume change from baseline
    End point 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
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    437
    433
    Units: percentage of brain volume loss
        arithmetic mean (confidence interval 95%)
    -0.29 (-0.35 to -0.23)
    -0.35 (-0.42 to -0.29)
    Statistical analysis title
    		 Brain volume loss
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.128
    Method
    		 random coefficient model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.15

    Secondary: Participants with confirmed relapse

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    End point title
    		 Participants with confirmed relapse
    End point 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).
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    469
    470
    Units: percentage of participants
        number (confidence interval 95%)
    16.51 (13.18 to 20.57)
    32.68 (28.10 to 37.79)
    No statistical analyses for this end point

    Secondary: Annualized relapse rate (ARR) >8 weeks after onset of treatment

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    End point title
    		 Annualized relapse rate (ARR) >8 weeks after onset of treatment
    End point 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).
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    461
    467
    Units: number of relapses in a year
        arithmetic mean (confidence interval 95%)
    0.096 (0.05 to 0.14)
    0.241 (0.16 to 0.32)
    No statistical analyses for this end point

    Secondary: 3-month confirmed disability worsening (3mCDW) based on EDSS > 8 weeks after onset of treatment - Pooled Data

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    End point title
    		 3-month confirmed disability worsening (3mCDW) based on EDSS > 8 weeks after onset of treatment - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    944
    932
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    9.4 (7.6 to 11.5)
    13.5 (11.4 to 16.0)
        Month 24 - from Kaplan Meier estimates
    10.9 (8.8 to 13.4)
    15.0 (12.6 to 17.7)
    Statistical analysis title
    		 3mCDW >8 weeks
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg - Pooled v TER 14 mg - Pooled
    Number of subjects included in analysis
    1876
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.002
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.641
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.486
         upper limit
    		 0.847

    Secondary: 6-month confirmed disability worsening (6mCDW) based on EDSS > 8 weeks after onset of treatment - Pooled Data

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    End point title
    		 6-month confirmed disability worsening (6mCDW) based on EDSS > 8 weeks after onset of treatment - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    944
    932
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18- from Kaplan Meier estimates
    7.8 (6.2 to 9.7)
    10.7 (8.9 to 13.0)
        Month 24 - from Kaplan Meier estimates
    8.1 (6.5 to 10.2)
    12.0 (9.9 to 14.5)
    Statistical analysis title
    		 6mCDW>8 weeks
    Statistical analysis description
    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.
    Comparison groups
    OMB 20 mg - Pooled v TER 14 mg - Pooled
    Number of subjects included in analysis
    1876
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.008
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.481
         upper limit
    		 0.898

    Secondary: 6-month confirmed cognitive decline on Symbol Digit Modalities Test (SDMT) - Pooled Data

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    End point title
    		 6-month confirmed cognitive decline on Symbol Digit Modalities Test (SDMT) - Pooled Data
    End point 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
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    930
    917
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    14.3 (12.2 to 16.8)
    13.7 (11.5 to 16.1)
        Month 24 - from Kaplan Meier estimates
    15.4 (13.1 to 18.2)
    14.0 (11.8 to 16.6)
    No statistical analyses for this end point

    Secondary: 6-month confirmed disability worsening (6mCDW) or 6-month confirmed cognitive decline (6mCCD) - Pooled Data

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    End point title
    		 6-month confirmed disability worsening (6mCDW) or 6-month confirmed cognitive decline (6mCCD) - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    941
    930
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    20.5 (18.0 to 23.4)
    21.7 (19.1 to 24.6)
        Month 24 - from Kaplan Meier estimates
    21.4 (18.8 to 24.3)
    22.6 (19.9 to 25.7)
    No statistical analyses for this end point

    Secondary: Change in cognitive performance measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data

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    End point title
    		 Change in cognitive performance measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    921
    909
    Units: scores
    arithmetic mean (confidence interval 95%)
        Month 6 n=921,909
    1.02 (0.46 to 1.59)
    0.64 (0.07 to 1.20)
        Month 12 n=879,863
    1.82 (1.22 to 2.41)
    1.70 (1.10 to 2.30)
        Month 18 n=849,808
    2.84 (2.24 to 3.45)
    2.05 (1.44 to 2.67)
        Month 24 n=492,468
    3.50 (2.80 to 4.20)
    2.39 (1.67 to 3.11)
        Month 30 n=156,117
    3.53 (2.39 to 4.68)
    2.97 (1.67 to 4.28)
    No statistical analyses for this end point

    Secondary: 6-month confirmed worsening of at least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data

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    End point title
    		 6-month confirmed worsening of at least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    936
    925
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    11.0 (9.1 to 13.3)
    10.4 (8.5 to 12.6)
        Month 24 - from Kaplan Meier estimates
    11.4 (9.5 to 13.8)
    10.6 (8.7 to 12.9)
    No statistical analyses for this end point

    Secondary: 6-month confirmed worsening of at least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data

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    End point title
    		 6-month confirmed worsening of at least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    932
    920
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    2.9 (2.0 to 4.3)
    3.3 (2.3 to 4.8)
        Month 24 - from Kaplan Meier estimates
    2.9 (2.0 to 4.3)
    3.3 (2.3 to 4.8)
    No statistical analyses for this end point

    Secondary: 6-month confirmed disability improvement (6mCDI) sustained until End of Study (EOS) as measured by EDSS - Pooled Data

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    End point title
    		 6-month confirmed disability improvement (6mCDI) sustained until End of Study (EOS) as measured by EDSS - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    749
    724
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    5.4 (4.0 to 7.4)
    4.6 (3.2 to 6.5)
        Month 24 - from Kaplan Meier estimates
    5.8 (4.2 to 7.8)
    4.6 (3.2 to 6.5)
    No statistical analyses for this end point

    Secondary: Number of new or enlarging T2 lesions on MRI per year from Month 12 until End of Study (EOS)

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    End point title
    		 Number of new or enlarging T2 lesions on MRI per year from Month 12 until End of Study (EOS)
    End point 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.
    End point type
    Secondary
    End point timeframe
    Month 12 up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    369
    348
    Units: T2 lesions per year
        arithmetic mean (confidence interval 95%)
    0.13 (0.09 to 0.18)
    3.84 (3.19 to 4.62)
    No statistical analyses for this end point

    Secondary: Percent change in T2 lesion volume relative to baseline

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    End point title
    		 Percent change in T2 lesion volume relative to baseline
    End point description
    Percent change from baseline in total T2 lesion volume
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    447
    437
    Units: percentage change in lesion volume
    arithmetic mean (standard deviation)
        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
    No statistical analyses for this end point

    Secondary: No evidence of disease activity (NEDA-4)

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    End point title
    		 No evidence of disease activity (NEDA-4)
    End point 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%.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    433
    427
    Units: percentage of participants
    number (confidence interval 95%)
        Month 12 n=433,427
    23.8 (19.8 to 27.8)
    17.8 (14.2 to 21.4)
        Month 24 n=92,78
    9.8 (3.7 to 15.9)
    5.1 (0.2 to 10.0)
    No statistical analyses for this end point

    Secondary: Multiple Sclerosis Impact Scale (MSIS-29) physical impact score change from baseline

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    End point title
    		 Multiple Sclerosis Impact Scale (MSIS-29) physical impact score change from baseline
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    473
    461
    Units: scores on a scale
    arithmetic mean (standard error)
        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
    No statistical analyses for this end point

    Secondary: Multiple Sclerosis Impact Scale (MSIS-29) psychological impact score change from baseline

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    End point title
    		 Multiple Sclerosis Impact Scale (MSIS-29) psychological impact score change from baseline
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    473
    461
    Units: scores on a scale
    arithmetic mean (standard error)
        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
    No statistical analyses for this end point

    Secondary: Annualized relapse rates (ARR) by NfL high-low subgroups - Pooled Data

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    End point title
    		 Annualized relapse rates (ARR) by NfL high-low subgroups - Pooled Data
    End point 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).
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    871
    841
    Units: number of relapses in a year
    arithmetic mean (confidence interval 95%)
        High > median n=443,410
    0.08 (0.07 to 0.11)
    0.21 (0.17 to 0.26)
        Low <= median n=428,431
    0.12 (0.09 to 0.15)
    0.23 (0.19 to 0.27)
    No statistical analyses for this end point

    Secondary: Number of new or enlarging T2 lesions per year by NfL high-low subgroups - Pooled Data

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    End point title
    		 Number of new or enlarging T2 lesions per year by NfL high-low subgroups - Pooled Data
    End point description
    Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate).
    End point type
    Secondary
    End point timeframe
    Baseline, yearly up to 2.5 years
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    850
    823
    Units: T2 lesions per year
    arithmetic mean (confidence interval 95%)
        High > median n=432,402
    0.95 (0.82 to 1.11)
    5.28 (4.61 to 6.03)
        Low <= median n=418,421
    0.39 (0.33 to 0.47)
    3.02 (2.64 to 3.46)
    No statistical analyses for this end point

    Secondary: Brain volume loss by NfL high-low subgroups - Pooled Data

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    End point title
    		 Brain volume loss by NfL high-low subgroups - Pooled Data
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 OMB 20 mg - Pooled TER 14 mg - Pooled
    Number of subjects analysed
    819
    794
    Units: percentage of brain volume loss
    arithmetic mean (confidence interval 95%)
        High > median n=416,387
    -0.32 (-0.38 to -0.26)
    -0.43 (-0.49 to -0.37)
        Low <= median n=403,407
    -0.24 (-0.30 to -0.18)
    -0.29 (-0.35 to -0.22)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) concentrations of ofatumumab

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    End point title
    		 Pharmacokinetic (PK) concentrations of ofatumumab [1]
    End point description
    Summary statistics of pharmacokinetic (PK) concentrations from trough samples collected within a 7-day window prior or at day of dosing.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12, 24, 48, 96
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No analysis was done
    End point values
    		 OMB 20 mg
    Number of subjects analysed
    481
    Units: ug/mL
    arithmetic mean (standard deviation)
        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
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    TER 14 mg
    Reporting group description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)

    Reporting group title
    OMB 20 mg
    Reporting 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)

    Serious adverse events
    		 TER 14 mg OMB 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 474 (7.81%)
    42 / 481 (8.73%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 474 (0.21%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 474 (0.21%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular infarction
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone contusion
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bundle branch block bilateral
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal arrhythmia
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 474 (0.00%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 474 (0.00%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 474 (0.00%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen sclerosus
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc compression
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 474 (0.21%)
    5 / 481 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 474 (0.42%)
    2 / 481 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 481 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 481 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TER 14 mg OMB 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    322 / 474 (67.93%)
    348 / 481 (72.35%)
    Investigations
    Blood immunoglobulin M decreased
         subjects affected / exposed
    8 / 474 (1.69%)
    31 / 481 (6.44%)
         occurrences all number
    10
    42
    Injury, poisoning and procedural complications
    Injection related reaction
         subjects affected / exposed
    66 / 474 (13.92%)
    119 / 481 (24.74%)
         occurrences all number
    148
    203
    Vascular disorders
    Hypertension
         subjects affected / exposed
    32 / 474 (6.75%)
    20 / 481 (4.16%)
         occurrences all number
    34
    22
    Nervous system disorders
    Headache
         subjects affected / exposed
    66 / 474 (13.92%)
    69 / 481 (14.35%)
         occurrences all number
    87
    128
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    32 / 474 (6.75%)
    25 / 481 (5.20%)
         occurrences all number
    36
    25
    Injection site reaction
         subjects affected / exposed
    26 / 474 (5.49%)
    61 / 481 (12.68%)
         occurrences all number
    46
    318
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    49 / 474 (10.34%)
    28 / 481 (5.82%)
         occurrences all number
    56
    31
    Nausea
         subjects affected / exposed
    32 / 474 (6.75%)
    30 / 481 (6.24%)
         occurrences all number
    43
    39
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 474 (5.06%)
    17 / 481 (3.53%)
         occurrences all number
    29
    20
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    75 / 474 (15.82%)
    27 / 481 (5.61%)
         occurrences all number
    78
    27
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    17 / 474 (3.59%)
    30 / 481 (6.24%)
         occurrences all number
    22
    33
    Depression
         subjects affected / exposed
    24 / 474 (5.06%)
    23 / 481 (4.78%)
         occurrences all number
    26
    26
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    30 / 474 (6.33%)
    22 / 481 (4.57%)
         occurrences all number
    35
    28
    Arthralgia
         subjects affected / exposed
    25 / 474 (5.27%)
    30 / 481 (6.24%)
         occurrences all number
    30
    35
    Back pain
         subjects affected / exposed
    24 / 474 (5.06%)
    35 / 481 (7.28%)
         occurrences all number
    26
    36
    Infections and infestations
    Influenza
         subjects affected / exposed
    28 / 474 (5.91%)
    27 / 481 (5.61%)
         occurrences all number
    29
    32
    Nasopharyngitis
         subjects affected / exposed
    88 / 474 (18.57%)
    88 / 481 (18.30%)
         occurrences all number
    132
    149
    Upper respiratory tract infection
         subjects affected / exposed
    47 / 474 (9.92%)
    52 / 481 (10.81%)
         occurrences all number
    62
    68
    Urinary tract infection
         subjects affected / exposed
    34 / 474 (7.17%)
    55 / 481 (11.43%)
         occurrences all number
    40
    81

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2017
    Amendment 1 was created at the request of several Health Authorities to provide additional guidance to the Investigators in regards to: switching to alternative disease modifying therapy for patients that have discontinued study drug and re-evaluation of benefit/risk of continuing study drug in patients, who experienced relevant progression of their disease (met criterion for 6-month confirmed disease worsening) while on study treatment.
    06 Aug 2018
    Amendment 2 was created to update the secondary objectives of the study and to provide clarification of the rescreening of patients. Modifications to the secondary objectives included: addition of endpoints related to NfL as secondary objectives and additional endpoint related to cognitive decline as measured on the SDMT, addition of composite endpoint related to physical disability and cognition, as measured by disability worsening on EDSS and cognitive decline on SDMT.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    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.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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