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    Clinical Trial Results:
    A Phase 3, randomized, double-blind efficacy and safety study comparing SAR442168 to teriflunomide (Aubagio®) in participants with relapsing forms of multiple sclerosis (GEMINI 2)

    Summary
    EudraCT number
    		 2020-000644-55
    Trial protocol
    		 FR   DE   GB   CZ   LV   SK   BE   NO   GR   NL   PT   HU   HR   IT   EE  
    Global end of trial date
    16 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2025
    First version publication date
    06 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC16034
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04410991
    WHO universal trial number (UTN)
    		 U1111-1238-1373
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    450 Water Street, Cambridge, Massachusetts, United States, 02141
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    30 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of daily tolebrutinib compared to a daily dose of 14 milligrams (mg) teriflunomide (Aubagio) measured by the annualized relapse rate (ARR) in participants with relapsing forms of multiple sclerosis (MS).
    Protection of trial subjects
    Participants were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trial, participants were provided with individual participant cards indicating the nature of the trial the participant is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jun 2020
    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: 33
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Brazil: 32
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Chile: 81
    Country: Number of subjects enrolled
    Croatia: 24
    Country: Number of subjects enrolled
    Czechia: 72
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    India: 26
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Latvia: 15
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Russian Federation: 99
    Country: Number of subjects enrolled
    Serbia: 37
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Spain: 55
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Türkiye: 12
    Country: Number of subjects enrolled
    Ukraine: 112
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 105
    Worldwide total number of subjects
    899
    EEA total number of subjects
    304
    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)
    899
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1093 participants were screened from 11-Jun-2020 to 08-Aug-2022, of which 194 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 899 participants were randomized in this study in a 1:1 ratio to either teriflunomide 14 mg or tolebrutinib 60 mg group. This was an event-driven (6-month confirmed disability worsening [CDW]) trial with a variable treatment duration (end-of-study [EOS] duration: up to approximately 48 months).

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Teriflunomide 14 mg
    Arm description
    		 Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to tolebrutinib was administered as a tablet orally QD up to approximately 48 months.

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    Aubagio
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg was administered as a tablet orally QD up to approximately 48 months.

    Arm title
    		 Tolebrutinib 60 mg
    Arm description
    		 Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to teriflunomide was administered as a tablet orally QD up to approximately 46 months.

    Investigational medicinal product name
    Tolebrutinib
    Investigational medicinal product code
    SAR442168
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tolebrutinib 60 mg was administered as a tablet orally QD up to approximately 46 months.

    Number of subjects in period 1
    		Teriflunomide 14 mg Tolebrutinib 60 mg
    Started
    452
    447
    Randomized and treated
    451
    447
    Completed
    378
    384
    Not completed
    74
    63
         Consent withdrawn by subject
    59
    55
         Poor compliance to protocol
    5
    4
         Unspecified
    10
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.

    Reporting group title
    Tolebrutinib 60 mg
    Reporting group description
    		 Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.

    Reporting group values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg Total
    Number of subjects
    		 452 447 899
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.1 ( 9.3 ) 36.6 ( 9.3 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 293 300 593
        Male
    		 159 147 306
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 19 23 42
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 11 7 18
        White
    		 417 411 828
        More than one race
    		 3 3 6
        Unknown or Not Reported
    		 2 3 5

    End points

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    End points reporting groups
    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.

    Reporting group title
    Tolebrutinib 60 mg
    Reporting group description
    		 Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.

    Primary: Annualized Relapse Rate as Assessed by Confirmed Protocol-defined Adjudicated Relapses

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    End point title
    		 Annualized Relapse Rate as Assessed by Confirmed Protocol-defined Adjudicated Relapses
    End point description
    The MS relapse was defined as a monophasic, acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for >=24 hours with or without recovery, present at normal body temperature, and preceded by >=30 days of clinical stability. The intent-to-treat (ITT) population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    452
    447
    Units: relapses per participant year
        number (confidence interval 95%)
    0.109 (0.088 to 0.134)
    0.108 (0.089 to 0.131)
    Statistical analysis title
    		 Annualized Relapse Rate
    Statistical analysis description
    Analysis was performed using negative binomial model with number of adjudicated relapses onset between randomization date and EOS date as the response variable, treatment group, Gadolinium (Gd)-enhancing T1 lesions at baseline (presence, absence), expanded disability status scale (EDSS) strata (<4, >=4) and geographic region (United States [US], non-US) as covariates, and log transformed observation duration as the offset variable.
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.9758 [2]
    Method
    		 Chi-squared
    Parameter type
    		 Relative risk
    Point estimate
    0.996
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.754
         upper limit
    		 1.315
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error.
    [2] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale

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    End point title
    		 Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
    End point description
    The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 6-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of >=1.5 points when the baseline score was 0, of >=1.0 point when the baseline score was 0.5 to <=5.5, of >=0.5 points when the baseline EDSS score was >5.5) over at least 6 months that was not attributable to another etiology. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    452
    447
    Units: months
        median (full range (min-max))
    12.14 (1.4 to 38.9)
    15.12 (2.0 to 37.1)
    Statistical analysis title
    		 Time to Onset of 6-Month CDW as Assessed by EDSS
    Statistical analysis description
    Analysis was performed using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (<4, >=4), geographic region (US, non-US).
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0114 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.582
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.891
    Notes
    [3] - A hierarchical testing procedure was used to control the overall type I error.
    [4] - Derived from log-rank test with stratification of EDSS strata (<4, >=4), geographic region (US, non-US).

    Secondary: Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale

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    End point title
    		 Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
    End point description
    The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 3-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of >=1.5 points when the baseline score was 0, of >=1.0 point when the baseline score was 0.5 to <=5.5, of >=0.5 points when the baseline EDSS score was >5.5) over at least 3 months that was not attributable to another etiology. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    452
    447
    Units: months
        median (full range (min-max))
    12.11 (1.4 to 39.1)
    12.11 (2.0 to 42.1)
    Statistical analysis title
    		 Time to Onset of 3-Month CDW as Assessed by EDSS
    Statistical analysis description
    Analysis was performed using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (<4, >=4), geographic region (US, non-US).
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0181 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.641
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.444
         upper limit
    		 0.925
    Notes
    [5] - A hierarchical testing procedure was used to control the overall type I error.
    [6] - Derived from log-rank test with stratification of EDSS strata (<4, >=4), geographic region (US, non-US).

    Secondary: Mean Number of new Gadolinium-Enhancing T1-Hyperintense Lesions per Scan

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    End point title
    		 Mean Number of new Gadolinium-Enhancing T1-Hyperintense Lesions per Scan
    End point description
    MRI of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions defined as the sum of the individual number of new Gd- enhancing T1-hyperintense lesions starting from baseline up to and including the EOS visit. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    452
    447
    Units: number of new Gd-enhancing T1 lesions
        arithmetic mean (confidence interval 95%)
    0.217 (0.169 to 0.280)
    0.460 (0.365 to 0.581)
    Statistical analysis title
    		 Number of new Gd-Enhancing T1-Hyperintense Lesions
    Statistical analysis description
    Analysis was performed using negative binomial model with the number of new Gd-enhancing T1-hyperintense lesions between randomization date and EOS date as the response variable, treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (<4, >=4) and geographic region (US, non-US) as covariates, and log transformed number of MRI scans as the offset variable.
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Relative risk
    Point estimate
    2.118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.502
         upper limit
    		 2.987
    Notes
    [7] - A hierarchical testing procedure was used to control the overall type I error.

    Secondary: Mean Number of new and/or Enlarging T2-Hyperintense Lesions per Year

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    End point title
    		 Mean Number of new and/or Enlarging T2-Hyperintense Lesions per Year
    End point description
    Magnetic resonance imaging (MRI) of the brain was performed to identify number of new and/or enlarging T2-hyperintense lesions defined as the sum of the individual number of new and/or enlarging T2 lesions starting from baseline up to and including the EOS visit. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    452
    447
    Units: number of new and/or enlarging T2lesions
        arithmetic mean (confidence interval 95%)
    4.369 (3.587 to 5.322)
    5.092 (4.340 to 5.975)
    Statistical analysis title
    		 Number of new/Enlarging T2-Hyperintense Lesions
    Statistical analysis description
    Analysis was performed using negative binomial model with the number of new and/or enlarging T2-hyperintense lesions between randomization date and EOS date as the response variable, treatment group, baseline T2-hyperintense lesion count, EDSS strata (<4, >=4) and geographic region (US, non-US) as covariates, and log transformed observation duration as the offset variable.
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.2362
    Method
    		 Chi-squared
    Parameter type
    		 Relative risk
    Point estimate
    1.165
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.905
         upper limit
    		 1.502
    Notes
    [8] - A hierarchical testing procedure was used to control the overall type I error.

    Secondary: Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS

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    End point title
    		 Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS
    End point description
    The SDMT was used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involved a simple substitution task using a reference key. The number of correct substitutions and number of items completed within a 90 second interval (maximum 110 seconds) were recorded. A decrease of 4 points from baseline on the SDMT was considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicating a better outcome. Baseline was defined as the last available value prior to the first dose of study intervention. Analysis was performed on the ITT population. Only participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 48 months)
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    359
    366
    Units: score on a scale
        least squares mean (standard error)
    0.428 ( 0.0373 )
    0.374 ( 0.0370 )
    Statistical analysis title
    		 Change From Baseline in Cognitive Function: SDMT
    Statistical analysis description
    Covariates in the mixed-effect model with repeated measures (MMRM) were treatment group, EDSS strata (<4, >=4), geographic region (US, non-US), visit, treatment by visit interaction, baseline value, and baseline value-by-visit interaction.
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    725
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.31
    Method
    		 MMRM
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.156
         upper limit
    		 0.05
    Notes
    [9] - A hierarchical testing procedure was used to control the overall type I error.

    Secondary: Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS

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    End point title
    		 Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS
    End point description
    The CVLT-II was a verbal learning and memory test consisting of recall and recognition of a list of 16 words. For each assessment, 5 trials were completed. Total Correct Recall Trials 1–5 was scaled to a normalized T–score metric, which had a mean of 50 and standard deviation of 10, the maximum possible score was 80 and a minimum was 0. Higher values indicated improved cognitive function. Baseline was defined as the last available value prior to the first dose of study intervention. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 48 months)
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    347
    357
    Units: T-score
        least squares mean (standard error)
    16.431 ( 0.6825 )
    15.819 ( 0.6740 )
    Statistical analysis title
    		 Change From Baseline in Cognitive Function:CVLT-II
    Statistical analysis description
    Covariates in the MMRM were treatment group, EDSS strata (<4, >=4), geographic region (US, non-US), visit, treatment by visit interaction, baseline value, and baseline value-by-visit interaction.
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.5235
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.612
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.493
         upper limit
    		 1.269
    Notes
    [10] - A hierarchical testing procedure was used to control the overall type I error.

    Secondary: Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale

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    End point title
    		 Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale
    End point description
    The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. CDI was defined as a decrease of >=1 point from baseline in the EDSS score lasting at least 6 months. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    452
    447
    Units: months
        median (full range (min-max))
    12.05 (2.8 to 30.6)
    9.04 (2.6 to 33.5)
    Statistical analysis title
    		 Time to Onset of 6-Month CDI as Assessed by EDSS
    Statistical analysis description
    Analysis was performed using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (<4, >=4), geographic region (US, non-US).
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0079 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.652
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.145
         upper limit
    		 2.383
    Notes
    [11] - A hierarchical testing procedure was used to control the overall type I error.
    [12] - Derived from log-rank test with stratification of EDSS strata (<4, >=4), geographic region (US, non-US).

    Secondary: Percent Change in Brain Volume Loss at EOS Compared to Month 6

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    End point title
    		 Percent Change in Brain Volume Loss at EOS Compared to Month 6
    End point description
    MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Month 6 to EOS (up to approximately 48 months)
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    307
    317
    Units: percent change
        least squares mean (standard error)
    -0.740 ( 0.0394 )
    -0.696 ( 0.0387 )
    Statistical analysis title
    		 Percent Change in Brain Volume Loss
    Statistical analysis description
    Covariates in the MMRM were treatment group, EDSS strata (<4, >=4), geographic region (US, non-US), visit, treatment by visit interaction, cube root transformed Month 6 brain volume, and cube root transformed Month 6 brain volume-by-visit interaction.
    Comparison groups
    Teriflunomide 14 mg v Tolebrutinib 60 mg
    Number of subjects included in analysis
    624
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.4266
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.044
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.065
         upper limit
    		 0.153
    Notes
    [13] - A hierarchical testing procedure was used to control the overall type I error.

    Secondary: Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS

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    End point title
    		 Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS
    End point description
    MSQoL-54 consisted of 12 subscales & 2 single-item measures(satisfaction with sexual function[1 item]; change in health[1 item]).12 subscales were:a:physical health(10 items), b:health perceptions(5 items), c:energy(5 items), d:role limit physical(4 items), e:sexual function(4 items), f:pain(3 items), g:social function(3 items), h:health distress(4 items), i:overall quality of life(2 items), j:emotional well-being(5 items), k:role limitations emotional(3 items) and l:cognitive function(4 items).Physical & mental health composite score were calculated as weighted sum of 'a to h' & 'i to l' subscales respectively. Each composite score was transformed linearly to common 0(worst) to 100(best) score range;higher score indicated improved QoL. Baseline=last available value prior to first dose of study intervention.Analysis was performed on ITT population.Only participants with data collected at specified timepoints are reported. n=number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 48 months)
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    357
    370
    Units: score on a scale
    least squares mean (standard error)
        Physical health composite score (n=353, 367)
    -1.040 ( 0.7404 )
    -1.199 ( 0.7304 )
        Mental health composite score (n=357, 370)
    -1.657 ( 0.8709 )
    -1.390 ( 0.8581 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs)
    End point description
    An AE was any untoward medical occurrence in participant or clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to Sponsor’s product or program for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. TEAEs were defined as AEs that developed, worsened or became serious during treatment period. Safety population included all randomized participants exposed to study intervention, regardless of amount of exposure, analyzed according to intervention actually received.
    End point type
    Secondary
    End point timeframe
    From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    451
    447
    Units: participants
        TEAEs
    387
    385
        TESAEs
    37
    49
        TEAEs:permanent study intervention discontinuation
    17
    19
        TEAESIs
    40
    46
    No statistical analyses for this end point

    Secondary: Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 like protein-1 (Chi3L1) Levels at EOS

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    End point title
    		 Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 like protein-1 (Chi3L1) Levels at EOS
    End point description
    Blood samples were collected at specified timepoints to assess change from baseline in NfL and Chi3L1. Baseline was defined as the last available value prior to the first dose of study intervention. The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 48 months)
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    311
    319
    Units: picogram/milliliter
    median (inter-quartile range (Q1-Q3))
        NfL (n=301, 314)
    -0.900 (-4.390 to 0.770)
    -0.150 (-3.560 to 2.750)
        Chi3L1 (n=311, 319)
    -281.100 (-6148.400 to 5647.000)
    1462.500 (-4578.600 to 7002.700)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS

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    End point title
    		 Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS
    End point description
    Blood samples were collected at specified timepoints to assess change from baseline in IgG and IgM levels. Baseline was defined as the last available value prior to the first dose of study intervention. The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints for the specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 48 months)
    End point values
    		 Teriflunomide 14 mg Tolebrutinib 60 mg
    Number of subjects analysed
    281
    287
    Units: gram per liter
    median (inter-quartile range (Q1-Q3))
        IgG
    -0.590 (-1.330 to 0.230)
    0.140 (-0.720 to 1.060)
        IgM
    -0.160 (-0.320 to -0.020)
    -0.320 (-0.530 to -0.150)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months.
    Adverse event reporting additional description
    Analysis was performed on the safety population. All-cause mortality was performed on the randomized population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Tolebrutinib 60 mg
    Reporting group description
    		 Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 46 months.

    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 48 months.

    Serious adverse events
    		 Tolebrutinib 60 mg Teriflunomide 14 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 447 (10.96%)
    37 / 451 (8.20%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oligodendroglioma
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 447 (0.22%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    2 / 447 (0.45%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma Necrosis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral Ischaemia
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Heavy Menstrual Bleeding
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenomyosis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abnormal Uterine Bleeding
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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
    Pneumonitis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide Attempt
         subjects affected / exposed
    4 / 447 (0.89%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatic Symptom Disorder
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Fatigue
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol Withdrawal Syndrome
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Transaminases Increased
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament Rupture
         subjects affected / exposed
    1 / 447 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun Shot Wound
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         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
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity To Various Agents
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Guillain-Barre Syndrome
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Paralysis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing Multiple Sclerosis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing-Remitting Multiple Sclerosis
         subjects affected / exposed
    2 / 447 (0.45%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis Acute
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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
    Calculus Urethral
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral Disorder
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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
    Pain In Extremity
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute Sinusitis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 447 (0.22%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Abscess
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 447 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Norovirus
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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 / 447 (0.00%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    0 / 447 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue Fever
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    2 / 447 (0.45%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    2 / 447 (0.45%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 447 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 447 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 447 (0.22%)
    0 / 451 (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
    		 Tolebrutinib 60 mg Teriflunomide 14 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    279 / 447 (62.42%)
    313 / 451 (69.40%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    20 / 447 (4.47%)
    23 / 451 (5.10%)
         occurrences all number
    23
    28
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 447 (2.91%)
    34 / 451 (7.54%)
         occurrences all number
    14
    35
    Nervous system disorders
    Headache
         subjects affected / exposed
    61 / 447 (13.65%)
    54 / 451 (11.97%)
         occurrences all number
    82
    64
    Paraesthesia
         subjects affected / exposed
    16 / 447 (3.58%)
    25 / 451 (5.54%)
         occurrences all number
    16
    30
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    10 / 447 (2.24%)
    34 / 451 (7.54%)
         occurrences all number
    14
    72
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 447 (6.71%)
    21 / 451 (4.66%)
         occurrences all number
    30
    22
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    22 / 447 (4.92%)
    49 / 451 (10.86%)
         occurrences all number
    25
    57
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    37 / 447 (8.28%)
    73 / 451 (16.19%)
         occurrences all number
    39
    74
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    24 / 447 (5.37%)
    28 / 451 (6.21%)
         occurrences all number
    25
    33
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 447 (5.15%)
    17 / 451 (3.77%)
         occurrences all number
    35
    21
    Back Pain
         subjects affected / exposed
    27 / 447 (6.04%)
    25 / 451 (5.54%)
         occurrences all number
    33
    39
    Infections and infestations
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 447 (4.25%)
    24 / 451 (5.32%)
         occurrences all number
    28
    26
    Urinary Tract Infection
         subjects affected / exposed
    25 / 447 (5.59%)
    30 / 451 (6.65%)
         occurrences all number
    35
    43
    Covid-19
         subjects affected / exposed
    106 / 447 (23.71%)
    115 / 451 (25.50%)
         occurrences all number
    126
    131
    Influenza
         subjects affected / exposed
    27 / 447 (6.04%)
    25 / 451 (5.54%)
         occurrences all number
    33
    35
    Nasopharyngitis
         subjects affected / exposed
    60 / 447 (13.42%)
    64 / 451 (14.19%)
         occurrences all number
    102
    97
    Upper Respiratory Tract Infection
         subjects affected / exposed
    31 / 447 (6.94%)
    36 / 451 (7.98%)
         occurrences all number
    43
    49

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2020
    The purpose of the amendment was to add exclusion criteria that were previously omitted and the regulatory requirement of a benefit-risk evaluation of the study in the context of the Coronavirus Disease 2019 (COVID-19) pandemic.
    24 Aug 2020
    The purpose of the amendment was to respond to European Health Authorities’ requests.
    28 Sep 2020
    The purpose of the amendment was to update the protocol for COVID-19-related contingencies.
    14 Apr 2021
    The purpose of the amendment was to update the liver function test frequency in the European Union countries in accordance with the updated teriflunomide (Aubagio) summary of product characteristics. Alanine aminotransferase (ALT) exclusion criterion was also updated to align with the Aubagio label.
    18 Nov 2021
    The purpose of the amendment was to update the safety follow-up algorithms for ALT increase and thrombocytopenia and the platelet level threshold for definition of an AESI in order to harmonize them with the other studies in the Phase 3 program.
    23 May 2022
    The purpose of the amendment was to update liver related exclusion criteria and monitoring to mitigate risk of drug-induced liver injury (DILI).
    13 Sep 2022
    The purpose of the amendment was to further reduce the risk of DILI by increasing the intensity of liver monitoring.
    12 Dec 2022
    The purpose of the amendment was to clarify information about DILI and update the ALT increase algorithm in relation to the risk of DILI.
    17 Nov 2023
    The purpose of the amendment was to update the testing requirements in the “Increase in ALT algorithm” as per Health Authority request.

    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.
    None reported
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    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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