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    Clinical Trial Results:
    A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis (HERCULES)

    Summary
    EudraCT number
    		 2020-000647-30
    Trial protocol
    		 BG   FR   DE   GB   CZ   NO   FI   DK   BE   LT   AT   GR   NL   PT   PL   HU   IT   RO  
    Global end of trial date
    29 Aug 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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC16645
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04411641
    WHO universal trial number (UTN)
    		 U1111-1246-7768
    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
    27 Sep 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of tolebrutinib compared to placebo in delaying disability progression in non-relapsing secondary progressive 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
    24 Sep 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: 26
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Belarus: 3
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Bulgaria: 60
    Country: Number of subjects enrolled
    Canada: 51
    Country: Number of subjects enrolled
    China: 24
    Country: Number of subjects enrolled
    Czechia: 40
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 107
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Greece: 27
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    India: 13
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Norway: 13
    Country: Number of subjects enrolled
    Poland: 87
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 22
    Country: Number of subjects enrolled
    Russian Federation: 103
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Türkiye: 36
    Country: Number of subjects enrolled
    Ukraine: 63
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 111
    Worldwide total number of subjects
    1131
    EEA total number of subjects
    629
    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)
    1131
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1131 participants were randomized in this study in a 2:1 ratio to receive either tolebrutinib or matching placebo in the double-blind (DB) period. Participants with 6-month confirmed disability progression (CDP) were given the option to receive open-label (OL) tolebrutinib.

    Pre-assignment
    Screening details
    		 This was an event-driven (6-month CDP) trial with a variable treatment duration (end-of-study [EOS] duration: up to approximately 47 months).

    Period 1
    Period 1 title
    DB 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
    		 DB: Placebo
    Arm description
    		 Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.
    Arm type
    		 Placebo

    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 orally once daily up to approximately 47 months.

    Arm title
    		 DB: Tolebrutinib 60 mg
    Arm description
    		 Participants received tolebrutinib 60 milligrams (mg) tablet orally once daily up to approximately 47 months.
    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 as a tablet orally once daily up to approximately 47 months.

    Number of subjects in period 1
    		DB: Placebo DB: Tolebrutinib 60 mg
    Started
    377
    754
    Completed
    192
    434
    Not completed
    185
    320
         Consent withdrawn by subject
    67
    122
         Adverse event, non-fatal
    13
    29
         Randomized and not treated
    2
    2
         Unspecified
    7
    27
         Poor compliance to protocol
    1
    5
         Progressive disease
    76
    116
         Lack of efficacy
    19
    19
    Period 2
    Period 2 title
    OL
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OL: Placebo/Tolebrutinib 60 mg
    Arm description
    		 Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
    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 optionally administered as a tablet orally once daily in OL up to approximately 39 months to those participants who received placebo in DB period and achieved 6-month CDP.

    Arm title
    		 OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg
    Arm description
    		 Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
    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 optionally administered as a tablet orally once daily in OL up to approximately 39 months to those participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP.

    Number of subjects in period 2 [1]
    		OL: Placebo/Tolebrutinib 60 mg OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg
    Started
    76
    120
    Completed
    67
    95
    Not completed
    9
    25
         Consent withdrawn by subject
    6
    17
         Adverse event, non-fatal
    1
    -
         Poor compliance to protocol
    1
    -
         Unspecified
    -
    6
         Progressive disease
    1
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only eligible participants switched to OL.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    DB: Placebo
    Reporting group description
    		 Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.

    Reporting group title
    DB: Tolebrutinib 60 mg
    Reporting group description
    		 Participants received tolebrutinib 60 milligrams (mg) tablet orally once daily up to approximately 47 months.

    Reporting group values
    		 DB: Placebo DB: Tolebrutinib 60 mg Total
    Number of subjects
    		 377 754 1131
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.9 ( 8.0 ) 48.9 ( 8.0 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 242 454 696
        Male
    		 135 300 435
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 19 36 55
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 6 10
        White
    		 348 703 1051
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 6 7 13

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    DB: Placebo
    Reporting group description
    		 Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.

    Reporting group title
    DB: Tolebrutinib 60 mg
    Reporting group description
    		 Participants received tolebrutinib 60 milligrams (mg) tablet orally once daily up to approximately 47 months.
    Reporting group title
    OL: Placebo/Tolebrutinib 60 mg
    Reporting group description
    		 Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.

    Reporting group title
    OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg
    Reporting group description
    		 Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.

    Primary: Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS)

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    End point title
    		 Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS)
    End point description
    The EDSS is a 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 multiple sclerosis [MS]) (0.5 increments from 1-10; next increase after 0 is 1). Higher scores indicated increased disability. Time to onset of 6-month CDP was defined as the time from randomization to the onset of a sustained increase from baseline in EDSS score of >=1.0 point from the baseline EDSS score when the baseline score was <=5.0 or of >=0.5 points when the baseline EDSS score was >5.0 confirmed after a minimum 6-month interval. 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) up to approximately 47 months
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    377
    754
    Units: months
        median (full range (min-max))
    11.97 (0.5 to 39.1)
    12.04 (2.8 to 37.4)
    Statistical analysis title
    		 Time to onset of 6-month CDP as assessed by EDSS
    Statistical analysis description
    Derived using Cox proportional-hazards model with robust variance estimation.Covariates were treatment group,age at screening (>40,<=40 years),geographic region (United States [US], non-US),baseline EDSS score & baseline gadolinium (Gd)-enhancing T1 lesions (presence, absence).In this analysis, for participants who completed study with 3-month confirmation and continued to meet disability progression criteria throughout EOS, their 6-month CDP status was imputed via multiple imputation method.
    Comparison groups
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0026 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.693
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.546
         upper limit
    		 0.88
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.
    [2] - Threshold for significance at 2-sided 0.05 level.

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

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    End point title
    		 Time to Onset of 3-month Confirmed Disability Progression as Assessed by Expanded Disability Status Scale
    End point description
    The EDSS is a 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. Time to onset of 3-month CDP was defined as the time from randomization to the onset of a sustained increase from baseline in EDSS score (of >=1.0 point from the baseline EDSS score when the baseline score is <=5.0, of >=0.5 points when the baseline EDSS score is >5.0) confirmed after a minimum 3-month interval. The confirmation of 3-month CDP followed the same criteria as that of 6-month CDP. 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) up to approximately 47 months
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    377
    754
    Units: months
        median (full range (min-max))
    11.96 (0.5 to 39.1)
    12.04 (2.8 to 39.5)
    Statistical analysis title
    		 Time to onset of 3-month CDP as assessed by EDSS
    Statistical analysis description
    Derived using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, age at screening (>40, <=40 years), geographic region (US, non-US), baseline EDSS score and baseline Gd-enhancing T1 lesions (presence, absence).
    Comparison groups
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0134 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.757
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.607
         upper limit
    		 0.944
    Notes
    [3] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.
    [4] - Threshold for significance at 2-sided 0.05 level.

    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 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) up to approximately 47 months
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    377
    754
    Units: number of T2 lesions
        arithmetic mean (confidence interval 95%)
    2.948 (2.239 to 3.880)
    1.835 (1.441 to 2.336)
    Statistical analysis title
    		 New/enlarging T2-hyperintense lesions per year
    Statistical analysis description
    Derived 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, age at screening (>40, <=40 years), geographic region (US, non-US), baseline EDSS score, and baseline number of T2 lesions as covariates, and log transformed observation duration as the offset variable.
    Comparison groups
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.011 [6]
    Method
    		 Chi-squared
    Parameter type
    		 Relative Risk
    Point estimate
    0.622
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.432
         upper limit
    		 0.897
    Notes
    [5] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.
    [6] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Time to Onset of Sustained 20% Increase in the 9-hole peg Test (HPT) for at Least 3 Months

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    End point title
    		 Time to Onset of Sustained 20% Increase in the 9-hole peg Test (HPT) for at Least 3 Months
    End point description
    The 9-HPT is a brief, standardized, quantitative test of upper extremity function and the time to complete the 9-HPT is used to assess a participant’s manual dexterity and fine motor skills. A participant was asked to place the pegs into the holes and remove them with the dominant and non-dominant hand; two successful trials for each hand. The amount of time (in seconds) required to place and remove all nine pegs was recorded for each trial (ranging from 10 to 300 seconds). The mean time to test completion served for assessment of the participant’s hand dexterity. Higher value indicated worse outcome. An increase of >20% from the baseline in the 9-HPT was considered meaningful worsening; time to onset of sustained 20% increase for at least 3 months is presented. 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) up to approximately 47 months
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    377
    754
    Units: months
        median (full range (min-max))
    12.39 (2.5 to 33.3)
    12.21 (2.8 to 39.2)
    Statistical analysis title
    		 9-hole HPT
    Statistical analysis description
    Derived using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, age at screening (>40, <=40 years), geographic region (US, non-US), baseline EDSS score and baseline Gd-enhancing T1 lesions (presence, absence).
    Comparison groups
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.8428 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.972
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.735
         upper limit
    		 1.286
    Notes
    [7] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.
    [8] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Time to Onset of Sustained 20% Increase in the Timed 25-foot Walk (T25-FW) for at Least 3 Months

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    End point title
    		 Time to Onset of Sustained 20% Increase in the Timed 25-foot Walk (T25-FW) for at Least 3 Months
    End point description
    The T25-FW test is a quantitative mobility and leg function performance test used to assess a participant’s walking ability. A participant was directed to one end of a clearly marked 25-foot course and instructed to walk 25 feet as quickly as safely possible for 2 trials. The amount of time (in seconds) to walk 25 feet was recorded (ranging from 2.2 to 180 seconds). The mean walk time was used for assessment of the participant’s walking ability. Higher value indicated worse outcome. An increase of >20% from the baseline in the T25-FW test was considered meaningful worsening; time to onset of sustained 20% increase for at least 3 months is presented. 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) up to approximately 47 months
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    377
    754
    Units: months
        median (full range (min-max))
    9.25 (2.5 to 36.3)
    9.54 (2.8 to 39.3)
    Statistical analysis title
    		 T25-FW
    Statistical analysis description
    Derived using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, age at screening (>40, <=40 years), geographic region (US, non-US), baseline EDSS score and baseline Gd-enhancing T1 lesions (presence, absence).
    Comparison groups
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.004
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.767
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.919
    Notes
    [9] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.

    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 is a 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. CDI was defined as a >=1 point decrease in the EDSS score from baseline confirmed over 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) up to approximately 47 months
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    377
    754
    Units: months
        median (full range (min-max))
    12.04 (3.0 to 24.1)
    11.89 (2.9 to 33.0)
    Statistical analysis title
    		 Time to onset of 6-month CDI as assessed by EDSS
    Statistical analysis description
    Derived using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, age at screening (>40, <=40 years), geographic region (US, non-US), baseline EDSS score and baseline Gd-enhancing T1 lesions (presence, absence).
    Comparison groups
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0206
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.882
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.102
         upper limit
    		 3.214
    Notes
    [10] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.

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

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    End point title
    		 Percent Change in Brain Volume at EOS Compared to Month 6
    End point description
    MRI of the brain was performed to evaluate percent change in brain volume which is considered as a marker of the central nervous system degenerative process. Least squares (LS) mean is presented. The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Month 6 to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    223
    451
    Units: percent change
        least squares mean (standard error)
    -0.776 ( 0.0479 )
    -0.694 ( 0.0336 )
    Statistical analysis title
    		 Percent change in brain volume (EOS to Month 6)
    Statistical analysis description
    Covariates in the mixed-effect model with repeated measures were treatment group, age at screening (>40, <=40 years), 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
    DB: Placebo v DB: Tolebrutinib 60 mg
    Number of subjects included in analysis
    674
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.1646
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.034
         upper limit
    		 0.197
    Notes
    [11] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the outcome measures are reported and continued when previous outcome measure was statistically significant at 2-sided 0.05. Primary and first 6 secondary endpoints are included in this procedure.

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

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    End point title
    		 Change From Baseline in Cognitive Function as Assessed by Symbol Digit Modalities Test (SDMT) at EOS
    End point description
    The SDMT is used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involves 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) are recorded. A decrease of 4 points from baseline on the SDMT is considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicated better outcome. LS mean is presented. Baseline was defined as the last available value prior to the first dose of study intervention. Analysis was performed on the ITT population. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    271
    546
    Units: score on a scale
        least squares mean (standard error)
    0.171 ( 0.0373 )
    0.136 ( 0.0264 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cognitive Function as Assessed by 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 California Verbal Learning Test Second Edition (CVLT-II) at EOS
    End point description
    The CVLT-II is a verbal learning and memory test consisting of recall and recognition of a list of 16 words. The list was read by the examiner, participants listened to the list and reported as many of the items as possible. For each assessment, 5 trials were completed. Standardized scores were used for analysis. The maximum possible score was 80 and a minimum was 0. A higher score indicated better recall meaning improved cognitive function. LS mean is presented. 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 those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    262
    531
    Units: score on a scale
        least squares mean (standard error)
    13.448 ( 0.9571 )
    14.169 ( 0.6759 )
    No statistical analyses for this end point

    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 consists of 12 subscales & 2 single-item measures (satisfaction with sexual function [1 item] & change in health [1 item].12 subscales:a:physical health (10 items),b:health perceptions (5 items), c:energy (5 items),d:role limitation 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 calculated as weighted sum of 'a to h' subscales and 'i to l' subscales respectively.Each composite score transformed linearly to common 0 (worst) to 100 (best) score range;LS mean presented.Higher score=improved QoL.Baseline:last available value prior to first dose of study intervention. Analyzed on ITT population.Only those participants with data collected at specified timepoints are reported.n=number of participants for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    268
    552
    Units: score on a scale
    least squares mean (standard error)
        Physical health composite score (n=262, 536)
    -3.979 ( 0.8032 )
    -3.455 ( 0.5623 )
        Mental health composite score (268, 552)
    -4.648 ( 0.9964 )
    -3.944 ( 0.6959 )
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (AEs), Treatment-emergent Serious AEs, Treatment-emergent AEs Leading to Permanent Study Intervention Discontinuation, and Treatment-emergent 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 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 Investigator to the Sponsor was required. TEAEs were defined as AEs that developed, worsened or became serious during TE period. The safety population included all randomized participants exposed to study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received.
    End point type
    Secondary
    End point timeframe
    From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months
    End point values
    		 DB: Placebo OL: Placebo/Tolebrutinib 60 mg DB: Tolebrutinib 60 mg OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg
    Number of subjects analysed
    375
    76
    752
    120
    Units: participants
        TEAEs
    293
    47
    613
    80
        TESAEs
    39
    9
    113
    11
        TEAEs:Permanent Study Intervention Discontinuation
    11
    1
    29
    0
        TEAESIs
    20
    6
    75
    10
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite

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    End point title
    		 Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite [12]
    End point description
    Blood samples were collected at specified timepoints to assess Tmax of tolebrutinib and M2 metabolite using a PopPK model. The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants who received tolebrutinib are included in this endpoint.
    End point values
    		 DB: Tolebrutinib 60 mg
    Number of subjects analysed
    669
    Units: hour (h)
    arithmetic mean (standard deviation)
        Tolebrutinib
    1.42 ( 0.674 )
        M2 Metabolite
    1.52 ( 0.667 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite [13]
    End point description
    Blood samples were collected at specified timepoints to assess Cmax of tolebrutinib and M2 metabolite using a population pharmacokinetics (PopPK) model. The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants who received tolebrutinib are included in this endpoint.
    End point values
    		 DB: Tolebrutinib 60 mg
    Number of subjects analysed
    669
    Units: nanogram/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Tolebrutinib
    9.94 ( 6.18 )
        M2 Metabolite
    27.5 ( 17.3 )
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite

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    End point title
    		 Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite [14]
    End point description
    Blood samples were collected at specified timepoints to assess AUC0-24 of tolebrutinib and M2 metabolite using a PopPK model. The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants who received tolebrutinib are included in this endpoint.
    End point values
    		 DB: Tolebrutinib 60 mg
    Number of subjects analysed
    669
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Tolebrutinib
    29.6 ( 17.8 )
        M2 Metabolite
    84.6 ( 53.7 )
    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 study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    171
    410
    Units: picogram/mL
    median (inter-quartile range (Q1-Q3))
        NfL (n=168, 403)
    1.070 (-1.285 to 3.615)
    1.900 (-0.370 to 4.470)
        Chi3L1 (n=171, 410)
    5156.900 (-1555.700 to 12099.200)
    3132.250 (-2822.100 to 13407.100)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS

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    End point title
    		 Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS
    End point description
    Blood samples were collected at specified timepoints to assess change from baseline in CD19+ B cells. 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 study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    26
    58
    Units: cells/microliter
        median (inter-quartile range (Q1-Q3))
    10.000 (-18.000 to 77.000)
    -63.000 (-105.000 to -8.000)
    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 study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to EOS (up to approximately 47 months)
    End point values
    		 DB: Placebo DB: Tolebrutinib 60 mg
    Number of subjects analysed
    149
    323
    Units: gram/liter
    median (inter-quartile range (Q1-Q3))
        IgG (n=149, 320)
    0.350 (-0.280 to 1.310)
    -0.085 (-0.845 to 0.665)
        IgM (n=142, 323)
    0.050 (-0.080 to 0.150)
    -0.240 (-0.450 to -0.120)
    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 end of follow-up, up to approximately 47 months
    Adverse event reporting additional description
    Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    DB: Placebo
    Reporting group description
    		 Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.

    Reporting group title
    OL: Tolebrutinib 60 mg/tolebrutinib 60 mg
    Reporting group description
    		 Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.

    Reporting group title
    OL: Placebo/tolebrutinib 60 mg
    Reporting group description
    		 Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.

    Reporting group title
    DB: Tolebrutinib 60 mg
    Reporting group description
    		 Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.

    Serious adverse events
    		 DB: Placebo OL: Tolebrutinib 60 mg/tolebrutinib 60 mg OL: Placebo/tolebrutinib 60 mg DB: Tolebrutinib 60 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 375 (10.40%)
    11 / 120 (9.17%)
    9 / 76 (11.84%)
    113 / 752 (15.03%)
         number of deaths (all causes)
    1
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign Neoplasm Of Thyroid Gland
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Myeloid Leukaemia
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer Stage 0, With Cancer In Situ
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial Adenocarcinoma
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Cancer Metastatic
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cell Carcinoma Stage I
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Assisted Suicide
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Rehabilitation Therapy
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait Disturbance
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rebound Effect
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acquired Hydrocele
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Murmur
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Vertebral Fracture
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Contusion
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 375 (0.27%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural Haematoma
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb Injury
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-Traumatic Pain
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shoulder Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull Fractured Base
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous Haematoma
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Haemothorax
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Liver Injury
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial Infarction
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain Hypoxia
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial Hypotension
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Oedema
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    8 / 752 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Pseudo Relapse
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle Spasticity
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic Neuritis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-Traumatic Headache
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinsonian Gait
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Restless Legs Syndrome
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Secondary Progressive Multiple Sclerosis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo Cns Origin
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute Vestibular Syndrome
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo Positional
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual Field Defect
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Functional Gastrointestinal Disorder
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive Pancreatitis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Terminal Ileitis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder Polyp
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondropathy
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 375 (0.27%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Pyelonephritis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    1 / 76 (1.32%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    8 / 752 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis Bacterial
         subjects affected / exposed
    2 / 375 (0.53%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 375 (0.80%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    5 / 752 (0.66%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    1 / 76 (1.32%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection Bacterial
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 375 (0.27%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Chronic
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 375 (0.00%)
    1 / 120 (0.83%)
    0 / 76 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella Zoster Pneumonia
         subjects affected / exposed
    0 / 375 (0.00%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 375 (0.80%)
    0 / 120 (0.00%)
    0 / 76 (0.00%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 375 (0.27%)
    2 / 120 (1.67%)
    0 / 76 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DB: Placebo OL: Tolebrutinib 60 mg/tolebrutinib 60 mg OL: Placebo/tolebrutinib 60 mg DB: Tolebrutinib 60 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    182 / 375 (48.53%)
    41 / 120 (34.17%)
    25 / 76 (32.89%)
    368 / 752 (48.94%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    19 / 375 (5.07%)
    3 / 120 (2.50%)
    0 / 76 (0.00%)
    25 / 752 (3.32%)
         occurrences all number
    22
    3
    0
    29
    Fall
         subjects affected / exposed
    40 / 375 (10.67%)
    6 / 120 (5.00%)
    4 / 76 (5.26%)
    70 / 752 (9.31%)
         occurrences all number
    54
    7
    4
    106
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 375 (7.20%)
    4 / 120 (3.33%)
    2 / 76 (2.63%)
    54 / 752 (7.18%)
         occurrences all number
    31
    4
    2
    79
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 375 (5.07%)
    2 / 120 (1.67%)
    0 / 76 (0.00%)
    49 / 752 (6.52%)
         occurrences all number
    21
    2
    0
    55
    Back Pain
         subjects affected / exposed
    24 / 375 (6.40%)
    3 / 120 (2.50%)
    1 / 76 (1.32%)
    47 / 752 (6.25%)
         occurrences all number
    25
    3
    1
    56
    Infections and infestations
    Influenza
         subjects affected / exposed
    13 / 375 (3.47%)
    5 / 120 (4.17%)
    2 / 76 (2.63%)
    41 / 752 (5.45%)
         occurrences all number
    14
    6
    2
    60
    Covid-19
         subjects affected / exposed
    85 / 375 (22.67%)
    14 / 120 (11.67%)
    4 / 76 (5.26%)
    185 / 752 (24.60%)
         occurrences all number
    96
    14
    4
    225
    Nasopharyngitis
         subjects affected / exposed
    26 / 375 (6.93%)
    8 / 120 (6.67%)
    2 / 76 (2.63%)
    70 / 752 (9.31%)
         occurrences all number
    35
    10
    3
    94
    Urinary Tract Infection
         subjects affected / exposed
    49 / 375 (13.07%)
    12 / 120 (10.00%)
    14 / 76 (18.42%)
    82 / 752 (10.90%)
         occurrences all number
    81
    19
    22
    152

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2020
    The overall rationale for this amended protocol consisted of regulatory requirements including addition of a relapse adjudication committee, change in stratification factor, removal of an endpoint and addition of a benefit-risk evaluation of the study in the context of the Coronavirus Disease 2019 pandemic.
    03 Nov 2020
    The overall rationale for this amended protocol was to respond to the feedback from Investigators with regard to the inclusion/exclusion criteria.
    26 Jul 2021
    The primary reason for this amendment was the availability of new information from drug-drug interaction studies.
    21 Dec 2021
    The primary reason for this amendment was to facilitate operational feasibility and reduce complexity, without compromising study integrity.
    23 May 2022
    The primary reason for this amended protocol was to update liver related exclusion criteria and monitor to mitigate risk of drug-induced liver injury (DILI).
    13 Sep 2022
    The rationale for this protocol amendment was to further reduce the risk of DILI by increasing the intensity of liver monitoring.
    14 Dec 2022
    The rationale for this protocol amendment was to clarify information about DILI and update the alanine aminotransferase (ALT) increase algorithm in relation to the risk of DILI.
    28 Sep 2023
    The rationale for this protocol amendment was to clarify the language and requirements for the use of OL tolebrutinib in participants who had achieved 6-month CDP and to update the testing requirements in the “increase in ALT algorithm” in accordance with the Council for International Organization of Medical Sciences working group on DILI consensus report.
    20 Nov 2023
    The rationale for this protocol amendment was to clarify the liver function monitoring requirements, update the testing requirements in the “increase in ALT algorithm”, and update the concomitant medications that were prohibited during the conduct of the study as per health authority request.
    20 Dec 2023
    The rationale for this protocol amendment was to update the liver function test monitoring 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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    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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