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    Clinical Trial Results:
    Long-term extension safety and efficacy study of SAR442168 in participants with relapsing multiple sclerosis

    Summary
    EudraCT number
    		 2018-004731-76
    Trial protocol
    		 FR   SK   CZ   EE   ES   NL  
    Global end of trial date
    26 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LTS16004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03996291
    WHO universal trial number (UTN)
    		 U1111-1223-4256
    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
    13 Dec 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the long-term safety and tolerability of tolebrutinib in participants with relapsing multiple sclerosis.
    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
    23 Sep 2019
    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
    Canada: 4
    Country: Number of subjects enrolled
    Czechia: 31
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    125
    EEA total number of subjects
    48
    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)
    125
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This long-term study was conducted at 37 centers in 9 countries. Of the 129 participants who completed the parent study DRI15928 (2018-003927-12), 126 were screened in this study from 23-Sep-2019 to 10-Mar-2020 of which 1 failed screening due to not meeting eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 125 participants were treated in this study which consisted of 2 parts: Part A (double-blind) and Part B (open-label). Part A was a short transition period until the dose of tolebrutinib to be used in Phase 3 was determined. In Part B, all participants formed a single dose group (the selected Phase 3 dose).

    Period 1
    Period 1 title
    Part A (double-blind period):39 weeks
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Tolebrutinib 5 mg
    Arm description
    		 Participants who received tolebrutinib 5 milligrams (mg) orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.
    Arm type
    		 Experimental

    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 5 mg was administered orally once daily as specified in the protocol.

    Arm title
    		 Part A: Tolebrutinib 15 mg
    Arm description
    		 Participants who received tolebrutinib 15 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.
    Arm type
    		 Experimental

    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 15 mg was administered orally once daily as specified in the protocol.

    Arm title
    		 Part A: Tolebrutinib 30 mg
    Arm description
    		 Participants who received tolebrutinib 30 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.
    Arm type
    		 Experimental

    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 30 mg was administered orally once daily as specified in the protocol.

    Arm title
    		 Part A: Tolebrutinib 60 mg
    Arm description
    		 Participants who received tolebrutinib 60 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.
    Arm type
    		 Experimental

    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 orally once daily as specified in the protocol.

    Number of subjects in period 1
    		Part A: Tolebrutinib 5 mg Part A: Tolebrutinib 15 mg Part A: Tolebrutinib 30 mg Part A: Tolebrutinib 60 mg
    Started
    31
    31
    32
    31
    Completed
    30
    31
    32
    31
    Not completed
    1
    0
    0
    0
         Unspecified
    1
    -
    -
    -
    Period 2
    Period 2 title
    Part B (open-label period):222 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part B: Tolebrutinib 5/60 mg
    Arm description
    		 Participants from Part A: tolebrutinib 5 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.
    Arm type
    		 Experimental

    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 orally once daily as specified in the protocol.

    Arm title
    		 Part B: Tolebrutinib 15/60 mg
    Arm description
    		 Participants from Part A: tolebrutinib 15 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.
    Arm type
    		 Experimental

    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 orally once daily as specified in the protocol.

    Arm title
    		 Part B: Tolebrutinib 30/60 mg
    Arm description
    		 Participants from Part A: tolebrutinib 30 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.
    Arm type
    		 Experimental

    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 orally once daily as specified in the protocol.

    Arm title
    		 Part B: Tolebrutinib 60/60 mg
    Arm description
    		 Participants from Part A: tolebrutinib 60 mg arm who provided consent switched to Part B and continued to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.
    Arm type
    		 Experimental

    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 orally once daily as specified in the protocol.

    Number of subjects in period 2
    		Part B: Tolebrutinib 5/60 mg Part B: Tolebrutinib 15/60 mg Part B: Tolebrutinib 30/60 mg Part B: Tolebrutinib 60/60 mg
    Started
    30
    31
    32
    31
    Completed
    20
    23
    20
    26
    Not completed
    10
    8
    12
    5
         Consent withdrawn by subject
    1
    -
    -
    -
         Adverse event, non-fatal
    1
    -
    1
    -
         Unspecified
    8
    7
    10
    5
         Poor compliance to protocol
    -
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Tolebrutinib 5 mg
    Reporting group description
    		 Participants who received tolebrutinib 5 milligrams (mg) orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 15 mg
    Reporting group description
    		 Participants who received tolebrutinib 15 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 30 mg
    Reporting group description
    		 Participants who received tolebrutinib 30 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 60 mg
    Reporting group description
    		 Participants who received tolebrutinib 60 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group values
    		 Part A: Tolebrutinib 5 mg Part A: Tolebrutinib 15 mg Part A: Tolebrutinib 30 mg Part A: Tolebrutinib 60 mg Total
    Number of subjects
    		 31 31 32 31 125
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.1 ( 9.9 ) 36.4 ( 9.4 ) 40.0 ( 9.9 ) 37.8 ( 9.0 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 23 20 20 23 86
        Male
    		 8 11 12 8 39
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 1 1 2 2 6
        White
    		 30 29 28 28 115
        More than one race
    		 0 1 0 0 1
        Unknown or Not Reported
    		 0 0 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Part A: Tolebrutinib 5 mg
    Reporting group description
    		 Participants who received tolebrutinib 5 milligrams (mg) orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 15 mg
    Reporting group description
    		 Participants who received tolebrutinib 15 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 30 mg
    Reporting group description
    		 Participants who received tolebrutinib 30 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 60 mg
    Reporting group description
    		 Participants who received tolebrutinib 60 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.
    Reporting group title
    Part B: Tolebrutinib 5/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 5 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Reporting group title
    Part B: Tolebrutinib 15/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 15 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Reporting group title
    Part B: Tolebrutinib 30/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 30 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Reporting group title
    Part B: Tolebrutinib 60/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 60 mg arm who provided consent switched to Part B and continued to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Subject analysis set title
    Tolebrutinib 5/60 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who received tolebrutinib 5 mg in Part A and tolebrutinib 60 mg in Part B were included in this arm.

    Subject analysis set title
    Tolebrutinib 15/60 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who received tolebrutinib 15 mg in Part A and tolebrutinib 60 mg in Part B were included in this arm.

    Subject analysis set title
    Tolebrutinib 30/60 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who received tolebrutinib 30 mg in Part A and tolebrutinib 60 mg in Part B were included in this arm.

    Subject analysis set title
    Tolebrutinib 60/60 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who received tolebrutinib 60 mg in Part A and tolebrutinib 60 mg in Part B were included in this arm.

    Primary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [1]
    End point description
    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An 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. TEAEs were defined as AEs that developed, worsened or became serious during the respective on-treatment periods. The safety population included all participants enrolled in this study and exposed to study drug, regardless of the amount of exposure.
    End point type
    Primary
    End point timeframe
    From first dose of study drug (Day 1) up to maximum exposure, 39 weeks in Part A and 222 weeks in Part B
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is reported.
    End point values
    		 Part A: Tolebrutinib 5 mg Part B: Tolebrutinib 5/60 mg Part A: Tolebrutinib 15 mg Part B: Tolebrutinib 15/60 mg Part A: Tolebrutinib 30 mg Part B: Tolebrutinib 30/60 mg Part A: Tolebrutinib 60 mg Part B: Tolebrutinib 60/60 mg
    Number of subjects analysed
    31
    30
    31
    31
    32
    32
    31
    31
    Units: participants
        TEAEs
    17
    26
    17
    29
    24
    27
    20
    27
        TESAEs
    0
    5
    2
    3
    1
    3
    2
    3
    No statistical analyses for this end point

    Secondary: Mean Number of new Gadolinium (Gd)-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192

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    End point title
    		 Mean Number of new Gadolinium (Gd)-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192
    End point description
    Magnetic resonance imaging (MRI) of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions. Central review was used to identify new Gd-enhancing T1-hyperintense lesions not present at the previous MRI. The modified intent-to-treat (mITT) population included all participants enrolled in this study who had at least 1 day of study drug exposure during study. As pre-specified in protocol and statistical analysis plan (SAP), the main objective of this study was to determine the long-term efficacy of selected Phase 3 dose (60 mg). Part A was a short transition period while picking phase 3 dose; no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60 and 60/60 mg. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Weeks 192 and 240
    End point values
    		 Tolebrutinib 5/60 mg Tolebrutinib 15/60 mg Tolebrutinib 30/60 mg Tolebrutinib 60/60 mg
    Number of subjects analysed
    21
    22
    19
    24
    Units: number of new Gd-enhancing T1 lesions
        arithmetic mean (standard deviation)
    0.24 ( 0.54 )
    0.36 ( 0.66 )
    0.32 ( 0.75 )
    0.13 ( 0.45 )
    No statistical analyses for this end point

    Secondary: Mean Number of new or Enlarging T2 Lesions at Week 240 Relative to Week 192

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    End point title
    		 Mean Number of new or Enlarging T2 Lesions at Week 240 Relative to Week 192
    End point description
    MRI of the brain was performed to identify number of new or enlarging T2 lesions. Central review was used to identify new or enlarging T2 lesions not present at the previous MRI; the values were standardized to per month values by dividing by the number of months (4-week intervals) from the previous MRI to the current MRI. Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and60/60 mg. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Weeks 192 and 240
    End point values
    		 Tolebrutinib 5/60 mg Tolebrutinib 15/60 mg Tolebrutinib 30/60 mg Tolebrutinib 60/60 mg
    Number of subjects analysed
    21
    23
    21
    26
    Units: number of new/enlarging T2 lesions
        arithmetic mean (standard deviation)
    3.86 ( 6.48 )
    4.43 ( 6.39 )
    1.81 ( 3.54 )
    2.85 ( 4.90 )
    No statistical analyses for this end point

    Secondary: Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192

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    End point title
    		 Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192
    End point description
    MRI of the brain was performed to identify number of Gd-enhancing T1-hyperintense lesions. Central review was used to identify Gd-enhancing T1-hyperintense lesions not present at the previous MRI. Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and60/60 mg. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Weeks 192 and 240
    End point values
    		 Tolebrutinib 5/60 mg Tolebrutinib 15/60 mg Tolebrutinib 30/60 mg Tolebrutinib 60/60 mg
    Number of subjects analysed
    21
    22
    19
    24
    Units: number of Gd-enhancing T1 lesions
        arithmetic mean (standard deviation)
    0.24 ( 0.54 )
    0.36 ( 0.66 )
    0.37 ( 0.76 )
    0.13 ( 0.45 )
    No statistical analyses for this end point

    Secondary: Annualized Relapse Rate (ARR)

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    End point title
    		 Annualized Relapse Rate (ARR)
    End point description
    Multiple sclerosis (MS) relapse was defined as acute, 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. ARR was the total number of relapses for participants by dose group divided by the sum of the standardized study duration for participants in the dose group. Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and60/60 mg.
    End point type
    Secondary
    End point timeframe
    From Baseline (enrollment in LTS16004, Day 1) to Week 240
    End point values
    		 Tolebrutinib 5/60 mg Tolebrutinib 15/60 mg Tolebrutinib 30/60 mg Tolebrutinib 60/60 mg
    Number of subjects analysed
    31
    31
    32
    31
    Units: relapses per participant year
        number (confidence interval 95%)
    0.26 (0.15 to 0.46)
    0.24 (0.14 to 0.42)
    0.28 (0.18 to 0.43)
    0.23 (0.13 to 0.38)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240

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    End point title
    		 Change from Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240
    End point description
    The EDSS is disability scale that assesses the following 7 functional domains: visual, brainstem, pyramidal (motor), cerebellar (coordination), sensory, cerebral, and bowel/bladder. The total EDSS ranges from 0 (normal) to 10 (death due to MS) (0.5 increments from 1-10; next increase after 0 is 1).Higher scores indicated increased disability. Baseline assessed for long-term tolebrutinib treatment by change from baseline: last non-missing value prior to the first administration of randomized study drug in DRI15928 study. Analysis performed on mITT population.As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3dose;no efficacy analysis was planned for this period alone; complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and 60/60 mg. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of DRI15928) and Week 240
    End point values
    		 Tolebrutinib 5/60 mg Tolebrutinib 15/60 mg Tolebrutinib 30/60 mg Tolebrutinib 60/60 mg
    Number of subjects analysed
    21
    23
    21
    26
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.10 ( 0.96 )
    0.24 ( 0.95 )
    0.38 ( 0.69 )
    0.29 ( 0.70 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events: From first dose of study drug (Day 1) up to maximum exposure, 39 weeks in Part A and 222 weeks in Part B. Deaths: From signing informed consent form (Week -6) up to end of follow-up, approximately 62 months
    Adverse event reporting additional description
    Analysis was performed on the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Part A: Tolebrutinib 5 mg
    Reporting group description
    		 Participants who received tolebrutinib 5 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 15 mg
    Reporting group description
    		 Participants who received tolebrutinib 15 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 30 mg
    Reporting group description
    		 Participants who received tolebrutinib 30 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part A: Tolebrutinib 60 mg
    Reporting group description
    		 Participants who received tolebrutinib 60 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined.

    Reporting group title
    Part B: Tolebrutinib 15/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 15 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Reporting group title
    Part B: Tolebrutinib 5/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 5 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Reporting group title
    Part B: Tolebrutinib 30/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 30 mg arm who provided consent switched to Part B to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Reporting group title
    Part B: Tolebrutinib 60/60 mg
    Reporting group description
    		 Participants from Part A: tolebrutinib 60 mg arm who provided consent switched to Part B and continued to receive the selected Phase 3 dose of tolebrutinib 60 mg orally once daily until Month 60.

    Serious adverse events
    		 Part A: Tolebrutinib 5 mg Part A: Tolebrutinib 15 mg Part A: Tolebrutinib 30 mg Part A: Tolebrutinib 60 mg Part B: Tolebrutinib 15/60 mg Part B: Tolebrutinib 5/60 mg Part B: Tolebrutinib 30/60 mg Part B: Tolebrutinib 60/60 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    3 / 31 (9.68%)
    5 / 30 (16.67%)
    3 / 32 (9.38%)
    3 / 31 (9.68%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint Dislocation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Polyp
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burn Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected Bite
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Tolebrutinib 5 mg Part A: Tolebrutinib 15 mg Part A: Tolebrutinib 30 mg Part A: Tolebrutinib 60 mg Part B: Tolebrutinib 15/60 mg Part B: Tolebrutinib 5/60 mg Part B: Tolebrutinib 30/60 mg Part B: Tolebrutinib 60/60 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 31 (38.71%)
    6 / 31 (19.35%)
    15 / 32 (46.88%)
    16 / 31 (51.61%)
    24 / 31 (77.42%)
    24 / 30 (80.00%)
    24 / 32 (75.00%)
    25 / 31 (80.65%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    4 / 32 (12.50%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    4
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    1
    Pyrexia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    1
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    1
    2
    Influenza Like Illness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    2
    0
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    2
    1
    Insomnia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    2
    2
    Injury, poisoning and procedural complications
    Foot Fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    2
    0
    Contusion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    1
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    4
    0
    Tension Headache
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    1
    2
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    Carpal Tunnel Syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    2
    Headache
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 31 (3.23%)
    4 / 32 (12.50%)
    3 / 31 (9.68%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
    2 / 32 (6.25%)
    3 / 31 (9.68%)
         occurrences all number
    3
    1
    4
    4
    2
    4
    2
    3
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    3 / 31 (9.68%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    1
    Diarrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    3
    Nausea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    1 / 31 (3.23%)
    3 / 30 (10.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    3
    1
    0
    Enteritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    Toothache
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    3
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    5 / 31 (16.13%)
         occurrences all number
    1
    0
    1
    1
    1
    1
    2
    5
    Back Pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    5 / 31 (16.13%)
    6 / 30 (20.00%)
    1 / 32 (3.13%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    1
    3
    7
    7
    1
    3
    Muscular Weakness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    4
    Myalgia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    3
    Pain In Extremity
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    3
    2
    1
    0
    1
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    2
    0
    Pharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    4 / 31 (12.90%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    2
    4
    2
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    3 / 32 (9.38%)
    2 / 31 (6.45%)
    6 / 31 (19.35%)
    5 / 30 (16.67%)
    4 / 32 (12.50%)
    6 / 31 (19.35%)
         occurrences all number
    0
    0
    3
    2
    11
    7
    6
    12
    Influenza
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    Cystitis Bacterial
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    3 / 32 (9.38%)
    5 / 31 (16.13%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    7
    14
    Cystitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    3 / 32 (9.38%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    3
    2
    Covid-19
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    10 / 31 (32.26%)
    10 / 30 (33.33%)
    7 / 32 (21.88%)
    14 / 31 (45.16%)
         occurrences all number
    0
    0
    0
    1
    12
    10
    9
    20
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    4 / 31 (12.90%)
    1 / 30 (3.33%)
    4 / 32 (12.50%)
    3 / 31 (9.68%)
         occurrences all number
    0
    4
    1
    0
    4
    2
    7
    3
    Urinary Tract Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    5 / 32 (15.63%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    6
    5
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    Tonsillitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    2
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    5 / 31 (16.13%)
    2 / 31 (6.45%)
    3 / 30 (10.00%)
    3 / 32 (9.38%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    1
    5
    2
    3
    3
    4
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Obesity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Aug 2019
    The protocol was primarily amended in response to comments from health authorities and ethics committees during the initial clinical trial application process. Furthermore, Sanofi Genzyme used that opportunity to update with new available information.
    02 Mar 2020
    It was based on the efficacy and safety findings from the DRI5928 trial which demonstrated that the dose of 60 mg taken with a meal was the most appropriate dose for further investigation. This was the recommended dose for Part B of this study (LTS16004). Furthermore, the Sponsor used this opportunity to update with new available information.
    29 Jul 2021
    The primary reason for this amendment was the availability of new information from drug-drug interaction studies.
    23 May 2022
    The primary driver for this amendment was to update the liver monitoring to mitigate risk of drug-induced liver injury (DILI) and to change the time between onsite visits to every 6 months after the Month 36 visit.
    12 Dec 2022
    The rationale for this protocol amendment was to clarify information about drug-induced liver injury and update the alanine aminotransferase (ALT) increase algorithm in relation to the risk of DILI.
    19 Jun 2023
    The rationale for this protocol amendment was to add the option for participants to continue to receive SAR442168 (tolebrutinib) in a separate clinical trial.
    16 Nov 2023
    The rationale for this protocol 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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