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    Clinical Trial Results:
    A Two Year, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of Teriflunomide Administered Orally Once Daily in Pediatric Patients With Relapsing Forms of Multiple Sclerosis Followed by an Open-label Extension

    Summary
    EudraCT number
    		 2011-005249-12
    Trial protocol
    		 EE   BE   ES   GR   PL   GB   FR   LT   Outside EU/EEA   IE   NL   BG   PT   SI   IT  
    Global end of trial date
    29 Jul 2024

    Results information
    Results version number
    		 v3(current)
    This version publication date
    04 Jan 2025
    First version publication date
    29 Jan 2021
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC11759
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02201108
    WHO universal trial number (UTN)
    		 U1111-1124-0983
    Sponsors
    Sponsor organisation name
    Genzyme, a Sanofi Company
    Sponsor organisation address
    50 Binney Street, Cambridge, Massachusetts, United States, 02142
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001094-PIP01-10
    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
    12 Sep 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of teriflunomide in comparison to placebo on disease activity as measured by time to first clinical relapse after randomisation in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia might have been used to minimise distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jul 2014
    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
    Spain: 1
    Country: Number of subjects enrolled
    Tunisia: 4
    Country: Number of subjects enrolled
    Türkiye: 32
    Country: Number of subjects enrolled
    Ukraine: 7
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    China: 37
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Lebanon: 4
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Morocco: 2
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Serbia: 2
    Worldwide total number of subjects
    166
    EEA total number of subjects
    33
    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)
    16
    Adolescents (12-17 years)
    150
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 57 active centres in 21 countries. A total of 185 subjects were screened between 16 July 2014 and 27 December 2017, of which 166 subjects were enrolled and randomised. A total of 19 subjects failed screening mainly due to meeting exclusion criteria.

    Pre-assignment
    Screening details
    		 Subjects were randomly assigned to receive either teriflunomide or placebo in a 2:1 ratio via Interactive Voice Response System. Randomisation was stratified by the country and subject's pubertal status.

    Period 1
    Period 1 title
    Double-blind Period (up to Week 96)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single tablet of placebo (matched to teriflunomide) was administered orally QD with or without food in the morning preferably at the same time each day of the double-blind treatment period (i.e., 96 weeks).

    Arm title
    		 Teriflunomide
    Arm description
    		 Subjects received 1 Teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (in case of BW greater than [>]40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=)95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per millilitre (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per millilitre (mcg*h/mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    AUBAGIO, HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide (3.5 mg or 7 mg or 14 mg) film-coated tablet was administered orally QD with or without food in the morning preferably at the same time each day of the double-blind treatment period (i.e., 96 weeks).

    Number of subjects in period 1
    		Placebo Teriflunomide
    Started
    57
    109
    Completed
    53
    102
    Not completed
    4
    7
         Consent withdrawn by subject
    2
    -
         Adverse Event
    -
    6
         Lack of efficacy
    2
    1
    Period 2
    Period 2 title
    Open Label Period (up to Week 192)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Teriflunomide
    Arm description
    		 Subjects previously treated with placebo during the double blind (DB) period received 1 teriflunomide tablet 3.5 mg (BW<=40 kg) or 7 mg teriflunomide (BW >40 kg) for first 8 weeks. After 8 weeks if predicted PK parameter was <= 95th percentile of adult range then subjects received 7 mg teriflunomide (BW<=40 kg) and 14 mg teriflunomide (BW>40 kg) in the open label (OL) period for 96 weeks (i.e., up to Week 192). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    AUBAGIO, HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide (3.5 mg or 7 mg or 14 mg) film-coated tablet was administered orally QD with or without food in the morning preferably at the same time each day.

    Arm title
    		 Teriflunomide / Teriflunomide
    Arm description
    		 Subjects previously treated with Teriflunomide during DB period continued receiving Teriflunomide in the OL period for additional 96 weeks (i.e., up to Week 192).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    AUBAGIO, HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide (3.5 mg or 7 mg or 14 mg) film-coated tablet was administered orally QD with or without food in the morning preferably at the same time each day.

    Number of subjects in period 2 [1]
    		Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Started
    52
    100
    Completed
    31
    73
    Not completed
    21
    27
         Adverse Event
    7
    5
         Other reason
    4
    7
         Poor compliance to protocol
    -
    1
         Lack of efficacy
    10
    14
    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: Post completion of DB period, only eligible subjects entered OL period.
    Period 3
    Period 3 title
    Extension Period (Up to Week 492)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Teriflunomide
    Arm description
    		 Subjects who were not adults when they completed the 192-week OL period were offered an optional additional extension period to receive 1 teriflunomide tablet 14 mg daily (or every other day if BW was <40 kg) until they became adults or until they were able to switch to the commercial product, whichever came first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    AUBAGIO, HMR1726
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide (14 mg) film-coated tablet was administered orally QD (or every other day if BW was <40 kg) with or without food in the morning preferably at the same time each day/every other day during the extension period (i.e., approximately 300 weeks)

    Number of subjects in period 3 [2]
    		Teriflunomide
    Started
    27
    Completed
    24
    Not completed
    3
         Adverse event, non-fatal
    2
         Poor compliance to protocol
    1
    Notes
    [2] - 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: Post completion of OL period, only eligible subjects entered the extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.

    Reporting group title
    Teriflunomide
    Reporting group description
    		 Subjects received 1 Teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (in case of BW greater than [>]40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=)95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per millilitre (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per millilitre (mcg*h/mL).

    Reporting group values
    		 Placebo Teriflunomide Total
    Number of subjects
    		 57 109 166
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.7 ( 2.1 ) 14.6 ( 2.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 72 111
        Male
    		 18 37 55
    Race
    Units: Subjects
        Caucasian/White
    		 42 75 117
        Black
    		 1 4 5
        Asian/Oriental
    		 12 25 37
        Other
    		 2 5 7

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.

    Reporting group title
    Teriflunomide
    Reporting group description
    		 Subjects received 1 Teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (in case of BW greater than [>]40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=)95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per millilitre (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per millilitre (mcg*h/mL).
    Reporting group title
    Placebo/Teriflunomide
    Reporting group description
    		 Subjects previously treated with placebo during the double blind (DB) period received 1 teriflunomide tablet 3.5 mg (BW<=40 kg) or 7 mg teriflunomide (BW >40 kg) for first 8 weeks. After 8 weeks if predicted PK parameter was <= 95th percentile of adult range then subjects received 7 mg teriflunomide (BW<=40 kg) and 14 mg teriflunomide (BW>40 kg) in the open label (OL) period for 96 weeks (i.e., up to Week 192). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.

    Reporting group title
    Teriflunomide / Teriflunomide
    Reporting group description
    		 Subjects previously treated with Teriflunomide during DB period continued receiving Teriflunomide in the OL period for additional 96 weeks (i.e., up to Week 192).
    Reporting group title
    Teriflunomide
    Reporting group description
    		 Subjects who were not adults when they completed the 192-week OL period were offered an optional additional extension period to receive 1 teriflunomide tablet 14 mg daily (or every other day if BW was <40 kg) until they became adults or until they were able to switch to the commercial product, whichever came first.

    Subject analysis set title
    Teriflunomide 7 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects with BW >40 kg received 1 Teriflunomide tablet, 7 mg orally QD for 8 weeks. After 8 weeks, based on subject's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).

    Subject analysis set title
    Teriflunomide 14 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    After 8 weeks, based on subject's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).

    Subject analysis set title
    Placebo / Teriflunomide 7 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects previously treated with placebo during the DB period received Teriflunomide 7 mg for 96 weeks in the OL period (i.e., up to Week 192).

    Subject analysis set title
    Placebo / Teriflunomide 14 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects previously treated with placebo during the DB period received Teriflunomide 14 mg for 96 weeks in OL period (i.e., up to Week 192).

    Subject analysis set title
    Teriflunomide / Teriflunomide 7 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects previously treated with Teriflunomide 7 mg during DB period continued receiving Teriflunomide 7 mg in the OL period for additional 96 weeks (i.e. up to Week 192).

    Subject analysis set title
    Teriflunomide / Teriflunomide 14 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects previously treated with Teriflunomide 14 mg during DB period continued receiving Teriflunomide 14 mg in the OL period for additional 96 weeks (i.e. up to Week 192).

    Primary: Time to First Confirmed Clinical Relapse

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    End point title
    		 Time to First Confirmed Clinical Relapse
    End point description
    Time to first clinical relapse:duration (in weeks) between randomisation & first confirmed clinical relapse. Clinical relapses:new/recurrent neurological symptoms not associated with fever/infection,lasted at least 24 hours & accompanied by new objective neurological findings upon neurological examination & documented by standardised, quantified functional system score (FSSs) which included 8 items:rated on different scales:brain stem, cerebellar & cerebral functions rated on scale of 0 to 5;visual, pyramidal, sensory & bowel/bladder rated on scale of 0 to 6 & ambulation on scale of 0 to 12 where higher score in each scale indicated worsened neurological function. Confirmed clinical relapse were reviewed & confirmed by independent Relapse Adjudication Panel. Subject without confirmed clinical relapse;considered as clinical relapse free until end of Week 96. Analysed on Intent-to-treat (ITT) population:all randomised subjects analysed according to treatment allocated by randomisation.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: weeks
        median (full range (min-max))
    39.14 (0.1 to 98.0)
    75.29 (0.1 to 98.7)
    Statistical analysis title
    		 Teriflunomide versus Placebo
    Statistical analysis description
    Hazard ratio (HR) was estimated using a Cox proportional-hazards model with factors for treatment group, region, pubertal status, age, and number of relapses in the year prior to randomisation as covariates and with robust variance estimation. Derived from log-rank test with stratification of region and pubertal status.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2949 [1]
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.388
         upper limit
    		 1.113
    Notes
    [1] - Threshold for significance was < 0.05.

    Secondary: Probability of Subjects Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192

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    End point title
    		 Probability of Subjects Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
    End point description
    Subject was considered free of clinical relapse if the subject had no confirmed clinical relapse before treatment discontinuation/completion in 192 weeks treatment period. Clinical relapses: new/recurrent neurological symptoms not associated with fever/infection, lasted at least 24 hours, & accompanied by new objective neurological findings upon neurological examination & documented by standardised, quantified FSSs which included 8 items: rated on different scales: brain stem, cerebellar & cerebral functions rated on scale of 0 to 5; visual, pyramidal, sensory & bowel/bladder rated on scale of 0 to 6 & ambulation on scale of 0 to 12, where higher score in each scale indicated worsened neurological function. New/recurrent symptoms occurred less than 30 days following onset of relapse were considered part of same relapse. Probability of subjects who were clinical relapse free at specified weeks was estimated by Kaplan-Meier method and reported. Analysed on efficacy population.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, 72, 96, 120, 144, 168 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: probability of relapse free subjects
    number (confidence interval 95%)
        Week 24
    0.750 (0.609 to 0.846)
    0.820 (0.730 to 0.883)
        Week 48
    0.596 (0.451 to 0.715)
    0.700 (0.600 to 0.780)
        Week 72
    0.519 (0.377 to 0.644)
    0.630 (0.528 to 0.716)
        Week 96
    0.442 (0.305 to 0.571)
    0.600 (0.497 to 0.688)
        Week 120
    0.404 (0.271 to 0.533)
    0.570 (0.467 to 0.660)
        Week 144
    0.365 (0.238 to 0.494)
    0.540 (0.437 to 0.631)
        Week 168
    0.365 (0.238 to 0.494)
    0.518 (0.416 to 0.611)
        Week 192
    0.365 (0.238 to 0.494)
    0.518 (0.416 to 0.611)
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192

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    End point title
    		 Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192
    End point description
    Volume of T2 lesions was measured by MRI scan. Analysis was performed on efficacy population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: millilitres
    arithmetic mean (standard deviation)
        DB Week 24 (n=40,88)
    3.0 ( 7.0 )
    0.5 ( 1.8 )
        DB Week 36 (n=19,39)
    4.6 ( 11.7 )
    4.4 ( 21.3 )
        DB Week 48 (n=21,68)
    0.5 ( 0.6 )
    -0.2 ( 3.4 )
        DB Week 72 (n=16,59)
    1.2 ( 1.6 )
    0.1 ( 1.9 )
        DB Week 96 (n=14,51)
    0.9 ( 1.4 )
    0.2 ( 1.9 )
        OL Week 48 (n=51,88)
    3.0 ( 9.7 )
    0.6 ( 8.8 )
        OL Week 96 (n=37,74)
    2.7 ( 8.1 )
    1.9 ( 4.0 )
        OL Week 144 (n=20,23)
    4.7 ( 10.7 )
    0.4 ( 17.1 )
        OL Week 192 (n=5,8)
    0.4 ( 9.4 )
    -3.6 ( 30.6 )
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan

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    End point title
    		 Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
    End point description
    Number of new or enlarged T2 lesions per scan was defined as the total number of new or enlarged T2 lesion that occurred during the 192 weeks treatment period divided by the total number of scans performed during 192 weeks. To account for the different numbers of scans performed among the subjects, a negative binomial regression model with robust variance estimation was used. The model included the total number of new or enlarged T2-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable. Analysis was performed on efficacy population which included all subjects enrolled and treated with at least 1 dose of teriflumomide in OL period analysed according to the treatment group allocated by randomisation in the DB period.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: lesions per scan
        number (confidence interval 95%)
    11.087 (6.586 to 18.662)
    5.664 (3.417 to 9.389)
    Statistical analysis title
    		 Plac/ Teri versus Teri/ Teri
    Comparison groups
    Placebo/Teriflunomide v Teriflunomide / Teriflunomide
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.511
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.343
         upper limit
    		 0.762

    Secondary: Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan

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    End point title
    		 Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan
    End point description
    The number of T1 Gd-Enhancing lesions per scan was defined as the total number of lesions that occurred during the 192 weeks treatment period divided by the total number of scans performed during 192 weeks. To account for the different number of scans performed among the subjects, a negative binomial regression model with robust variance estimation was used. The model included the total number of T1-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable. Analysis was performed on efficacy population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: lesions per scan
        number (confidence interval 95%)
    2.686 (1.263 to 5.712)
    1.532 (0.624 to 3.762)
    Statistical analysis title
    		 Plac/ Teri versus Teri/ Teri
    Comparison groups
    Placebo/Teriflunomide v Teriflunomide / Teriflunomide
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.331
         upper limit
    		 0.983

    Secondary: Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions

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    End point title
    		 Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions
    End point description
    Volume of T1 hypointense lesions was measured by MRI scan. Analysis was performed on efficacy population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: millilitres
    arithmetic mean (standard deviation)
        DB Week 24 (n=40,88)
    0.3 ( 1.3 )
    0.0 ( 0.7 )
        DB Week 36 (n=19,39)
    0.8 ( 1.8 )
    0.2 ( 0.8 )
        DB Week 48 (n=20,68)
    0.2 ( 0.4 )
    0.4 ( 2.9 )
        DB Week 72 (n=16,58)
    0.1 ( 0.7 )
    0.1 ( 0.6 )
        DB Week 96 (n=14,50)
    0.1 ( 0.6 )
    0.1 ( 0.7 )
        OL Week 48 (n=51,86)
    0.7 ( 1.9 )
    0.5 ( 1.4 )
        OL Week 96 (n=37,73)
    1.0 ( 2.0 )
    0.6 ( 1.9 )
        OL Week 144 (n=20,22)
    2.0 ( 3.0 )
    1.9 ( 3.4 )
        OL Week 192 (n=5,8)
    4.0 ( 5.8 )
    2.5 ( 5.7 )
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging Assessment: Percentage of Subjects Free of New or Enlarged MRI T2-Lesions

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    End point title
    		 Magnetic Resonance Imaging Assessment: Percentage of Subjects Free of New or Enlarged MRI T2-Lesions
    End point description
    Percentage of subjects who were free of new or enlarged T2 lesions at Weeks 24, 48, 72, 96, 144 and 192 were reported. Analysis was performed on efficacy population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72, 96, 144 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: percentage of subjects
    number (not applicable)
        Week 24
    86.5
    86.0
        Week 48
    32.7
    25.0
        Week 72
    15.4
    17.0
        Week 96
    15.4
    16.0
        Week 144
    11.5
    14.0
        Week 192
    7.7
    9.0
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan

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    End point title
    		 Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan
    End point description
    The number of new T1 hypointense lesions were obtained from MRI scans. Analysis was performed on efficacy population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: lesions
        number (not applicable)
    1561
    1910
    Statistical analysis title
    		 Plac/ Teri versus Teri/ Teri
    Comparison groups
    Placebo/Teriflunomide v Teriflunomide / Teriflunomide
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.498
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.296
         upper limit
    		 0.836

    Secondary: Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192

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    End point title
    		 Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192
    End point description
    Percent change from baseline in brain volume (assessed using MRI scans of the Brain) at Weeks 24, 36, 48, 72, 96, 144 and 192 was reported. Analysis was performed on efficacy population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: percent change
    arithmetic mean (standard deviation)
        DB Week 24 (n=38,83)
    -0.3 ( 0.7 )
    -0.2 ( 0.7 )
        DB Week 36 (n=17,39)
    -0.7 ( 0.7 )
    -0.4 ( 1.0 )
        DB Week 48 (n=20,64)
    -0.6 ( 1.1 )
    -0.5 ( 0.9 )
        DB Week 72 (n=16,53)
    -0.9 ( 1.3 )
    -0.6 ( 1.1 )
        DB Week 96 (n=13,47)
    -0.9 ( 1.3 )
    -0.8 ( 1.1 )
        OL Week 48 (n=43,73)
    -1.4 ( 1.6 )
    -1.1 ( 1.3 )
        OL Week 96 (n=33,60)
    -1.8 ( 1.9 )
    -1.4 ( 1.6 )
        OL Week 144 (n=16,17)
    -3.1 ( 2.8 )
    -2.0 ( 1.7 )
        OL Week 192 (n=4,6)
    -2.2 ( 1.2 )
    -3.0 ( 1.9 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72, 96, 120, 144, 168 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
    End point description
    SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The SDMT score is the number of correct substitution and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function. Analysis was performed on efficacy population. Here, ‘n’ = number of subjects analysed for each specified category. Here, '99999' is used as a space filler which specifies that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, DB period: Weeks 24, 48, 72 and 96; OL period: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: score on a scale
    arithmetic mean (standard deviation)
        DB Week 24 (n=40,85)
    5.1 ( 12.0 )
    4.6 ( 9.1 )
        DB Week 48 (n=20,64)
    7.3 ( 14.1 )
    5.7 ( 10.3 )
        DB Week 72 (n=17,58)
    6.4 ( 12.9 )
    5.6 ( 11.5 )
        DB Week 96 (n=14,52)
    8.8 ( 10.7 )
    8.1 ( 11.1 )
        OL Week 24 (n=51,91)
    6.3 ( 13.9 )
    8.3 ( 12.3 )
        OL Week 48 (n=44,88)
    6.7 ( 13.3 )
    7.6 ( 13.0 )
        OL Week 72 (41,76)
    8.0 ( 15.5 )
    9.2 ( 13.0 )
        OL Week 96 (n=36,73)
    7.6 ( 16.7 )
    8.0 ( 14.8 )
        OL Week 120 (n=22,28)
    3.7 ( 15.9 )
    7.2 ( 10.3 )
        OL Week 144 (n=18,19)
    6.6 ( 14.4 )
    5.2 ( 13.0 )
        OL Week 168 (n=13,15)
    3.5 ( 17.9 )
    1.7 ( 14.0 )
        OL Week 192 (n=1,4)
    12.0 ( 99999 )
    -0.3 ( 18.2 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72, 96, 120, 144, 168 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
    End point description
    SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The SDMT score is the number of completed items and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function. Analysis was performed on efficacy population. Here, ‘n’ = number of subjects analysed for each specified category. Here, '99999' was used as a space filler which specifies that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, DB period: Weeks 24, 48, 72 and 96; OL period: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: score on a scale
    arithmetic mean (standard deviation)
        DB Week 24 (n=40,85)
    3.8 ( 11.7 )
    3.6 ( 9.0 )
        DB Week 48 (n=20,64)
    6.3 ( 13.8 )
    4.7 ( 10.3 )
        DB Week 72 (n=17,58)
    5.1 ( 13.4 )
    4.5 ( 11.4 )
        DB Week 96 (n=14,52)
    7.1 ( 11.2 )
    6.9 ( 11.1 )
        OL Week 24 (n=51,91)
    4.8 ( 13.5 )
    7.1 ( 12.4 )
        OL Week 48 (n=44,88)
    5.5 ( 12.8 )
    6.4 ( 13.0 )
        OL Week 72 (n=41,76)
    6.4 ( 15.4 )
    8.1 ( 12.8 )
        OL Week 96 (n=36,73)
    6.3 ( 16.6 )
    7.6 ( 12.5 )
        OL Week 120 (n=22,28)
    3.7 ( 14.7 )
    6.3 ( 11.5 )
        OL Week 144 (n=18,19)
    4.8 ( 15.1 )
    3.7 ( 13.4 )
        OL Week 168 (n=13,15)
    2.7 ( 15.5 )
    -0.3 ( 15.6 )
        OL Week 192 (n=1,4)
    12.0 ( 99999 )
    -1.5 ( 18.3 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Weeks 96 and 192
    End point description
    'Trail Making Test Part A' is a neuropsychological test of visual attention and task switching. The task requires a subject to 'connect-the-dots' of 25 consecutive numbers (1, 2, 3,etc.) in sequential order on a sheet of paper or computer screen. The goal of the subject is to finish the test as quickly as possible, and the time taken to complete the test used as the primary performance metric (in seconds). This is a timed test and the number of seconds to complete the task is recorded. Maximum time allowed is 300 seconds. A lower score indicated better cognitive function. Analysis was performed on efficacy population. Here, ‘number of subjects analysed’ = number of subjects evaluable for this endpoint and "n"= number of subjects evaluable for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    8
    21
    Units: seconds
    arithmetic mean (standard deviation)
        Week 96 (n=3,13)
    8.4 ( 9.0 )
    -3.1 ( 19.5 )
        Week 192 (n=8,21)
    6.3 ( 20.7 )
    -6.6 ( 17.4 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192
    End point description
    TMT-B is a cognitive test that gives a measure of various aspects of cognitive performance. It is used to measure cognitive fatigue. The test consists of 25 circles containing 13 sequential numbers (1-13) and 12 sequential letters (A-L) positioned. The test evaluates the time (in seconds) to correctly order letters and numbers in alternate order (1, A, 2, B etc.). Maximum time allowed is 300 seconds, where less time/lower score indicates better cognitive function/performance. Analysis was performed on efficacy population. Here, "number of subjects analysed"= subjects evaluable for this endpoint and ‘n’ = number of subjects evaluable for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    8
    21
    Units: seconds
    arithmetic mean (standard deviation)
        Week 96 (n=3,13)
    -19.8 ( 33.7 )
    -29.5 ( 56.6 )
        Week 192 (n=8,21)
    -37.0 ( 83.3 )
    -18.8 ( 37.3 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192
    End point description
    The BVMT consists of three trials in which subjects must recall shapes by drawing figures on a blank page (response booklet) after being given the opportunity to memorise the figures (given in BMVT-R form) for 10 seconds. BMVT-R form consists of six figures. Points are awarded based on the accuracy of the drawn figure and by correct placement on the blank page. A minimum of 0 to 12 points/scores are awarded per trial, so a subject can score between 0 and 36 points for all three trials (by adding the points/score from each trial), where higher score indicates better outcome. Analysis was performed on ITT population which included all randomised subjects analysed according to the treatment group allocated by randomization . Here, ‘number of subject analysed’ = number of subjects evaluable for this endpoint and "n"= subjects evaluable for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    16
    45
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 96 (n=5,35)
    -0.8 ( 9.3 )
    1.6 ( 5.3 )
        Week 192 (n=16,45)
    1.0 ( 6.9 )
    1.2 ( 5.4 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192
    End point description
    The Beery VMI is a non-verbal assessment that assessed the extent to which individuals can integrate their visual and motor abilities. The subjects were provided with geometric designs ranging from simple line drawings to more complex figures and were asked to copy the designs. The test consisted of 24 figures. One point was scored for each successful copy of drawings and no scoring was given when the subject failed to copy the drawings properly. Each successful copying of drawings was summed up and the total was scored on a scale ranged from 0 to 24, where higher score indicated better visual construction skills/better visual and motor abilities and lower score indicated poor visual construction skills/poor visual and motor abilities. Analysis was performed on efficacy population. Here, "number of subjects analysed" = subjects evalauble for this endpoint and 'n’ = number of subjects evaluable for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    26
    58
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 96 (n=10,49)
    0.6 ( 2.4 )
    -0.4 ( 4.8 )
        Week 192 (n=26,58)
    0.1 ( 5.4 )
    0.4 ( 2.9 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192
    End point description
    The WASI-II: Vocabulary test is a quick estimate of an individual’s level of intellectual functioning which comprised of 31 total items that require the subject to orally define 3 images and 28 words presented both orally and visually. Items 1 to 3 rated on a score of 0 or 1, items 4 and 5 rated on a score of 0 or 2, items 6 to 31 rated on a scale of 0 to 2. Each item score was summed up to derive the total score which was ranged from 0 (minimum score) to 59 (maximum score), where higher score indicated better level of intellectual functioning/higher level of intelligence. Analysis was performed on efficacy population. Here, "number of subjects analysed" = subjects evalauble for this endpoint. Here, "99999" was used as a space filler which specifies that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    1
    1
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 96
    5.0 ( 99999 )
    4.0 ( 99999 )
        Week 192
    3.0 ( 99999 )
    5.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192
    End point description
    Letter fluency is a condition measured in Delis-Kaplan Executive Function System (D-KEFS). Subjects are asked to name as many words as they can, starting with a specified letter for 60 seconds. The words cannot be names, places, numbers or grammatical variants of previous answers. Repeated answers are not scored as a correct response. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials and a letter fluency score is given. A higher score is considered better. There is no set range as the score depends on how many correct words the subject relays in the given time period. Analysis was performed on efficacy population. Here, “number of subjects analysed”= number of subjects evaluable for this endpoint. Here, 99999 was used as a space filler which specifies that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    1
    2
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 96
    -3.0 ( 99999 )
    4.0 ( 9.9 )
        Week 192
    5.0 ( 99999 )
    -6.5 ( 16.3 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192
    End point description
    SRT is a test to assess verbal learning and memory. During the administration of the SRT only the examiner and the subject should be in the testing room. A list of twelve words is read aloud by the examiner at a rate of one word per two seconds. The subject is asked to recall all twelve words after a 30 minute delay. Only the words that are missed on the preceding trial are given in the consecutive trial. The total score represents a sum score of total 6 trials, therefore the range is from 0-72. The lower the value the worse the outcome, higher value indicates better recall. Analysis was performed on efficacy population. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n”= number of subjects evaluable for each specified category. Here, "99999" was used as a space filler and specified that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    1
    2
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 96 (n=1,2)
    1.0 ( 99999 )
    -0.5 ( 2.1 )
        Week 192 (n=1,1)
    0.0 ( 99999 )
    0.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192

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    End point title
    		 Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192
    End point description
    Category fluency is a condition measured in the D-KEFS. It measures subject's ability to generate words from three different categories (e.g., fruits, vegetables and animals), within a minute for each category. Total score is number of correct words for each category with no points for repetitions or non-words. Score range 0 to unlimited, where 0 = low score, higher score indicates better performance. Analysis was performed on efficacy population. Here, “number of subjects analysed”= number of subjects evaluable for this endpoint. Here, '99999' was used as a space filler and specified that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 96 and 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    1
    2
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 96
    6.0 ( 99999 )
    5.0 ( 5.7 )
        Week 192
    -2.0 ( 99999 )
    -13.5 ( 17.7 )
    No statistical analyses for this end point

    Secondary: OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide

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    End point title
    		 OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
    End point description
    Ctrough was defined as the concentration reached by the drug before the next dose is administered. Data for this endpoint was planned to be collected and analysed separately for each dose of teriflunomide. Analysis was performed on PK population which included all randomised subjects exposed to study medication, regardless of the amount of treatment administered who had at least one PK sample taken. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 36
    End point values
    		 Placebo / Teriflunomide 7 mg Placebo / Teriflunomide 14 mg Teriflunomide / Teriflunomide 7 mg Teriflunomide / Teriflunomide 14 mg
    Number of subjects analysed
    12
    31
    2
    79
    Units: micrograms per millilitre
        arithmetic mean (standard deviation)
    45.8 ( 35.3 )
    50.4 ( 23.8 )
    33.7 ( 10.7 )
    63.6 ( 35.5 )
    No statistical analyses for this end point

    Secondary: DB: Pharmacokinetics (PK): Steady-state Trough Concentration (Ctrough) of Teriflunomide

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    End point title
    		 DB: Pharmacokinetics (PK): Steady-state Trough Concentration (Ctrough) of Teriflunomide
    End point description
    Ctrough was defined as the concentration reached by the drug before the next dose is administered. Data for this endpoint was planned to be collected and analysed separately for each dose of teriflunomide. Analysis was performed on PK population which included all randomised subjects exposed to double-blind study medication and had at least 1 PK sample taken. PK samples for teriflunomide 3.5 mg were collected during the first 8 weeks but all subjects were switched to teriflunomide 7 mg after Week 8. Hence, plasma concentration of teriflunomide 7 mg and 14 mg were reported. Here, ‘number of subjects analysed’=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Week 36
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg
    Number of subjects analysed
    10
    66
    Units: micrograms per millilitre
        arithmetic mean (standard deviation)
    53.1 ( 25.3 )
    67.8 ( 41.7 )
    No statistical analyses for this end point

    Secondary: OL: Time to First Confirmed Clinical Relapse

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    End point title
    		 OL: Time to First Confirmed Clinical Relapse
    End point description
    Time to first clinical relapse: duration (in weeks) after enrollment in OL period & first confirmed clinical relapse. Clinical relapses: new/recurrent neurological symptoms not associated with fever/infection, lasted at least 24hours & accompanied by new objective neurological findings upon neurological examination & documented by standardised, quantified FSSs which included 8 items: rated on different scales: brain stem, cerebellar & cerebral functions rated on scale of 0 to 5;visual, pyramidal, sensory &bowel/bladder rated on scale of 0 to 6 & ambulation on scale of 0 to 12 where higher score in each scale indicated worsened neurological function. Confirmed clinical relapse were reviewed & confirmed by independent Relapse Adjudication Panel. Subject without confirmed clinical relapse; considered as clinical relapse free until end of Week 192. Analysed on efficacy population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 192
    End point values
    		 Placebo/Teriflunomide Teriflunomide / Teriflunomide
    Number of subjects analysed
    52
    100
    Units: weeks
        median (full range (min-max))
    95.86 (0.6 to 176.0)
    96.00 (1.0 to 183.4)
    Statistical analysis title
    		 Plac/ Teri versus Teri/ Teri
    Comparison groups
    Placebo/Teriflunomide v Teriflunomide / Teriflunomide
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.693
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.296

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs),serious TEAEs and deaths:From first (1st) dose of drug up to 96 weeks (DB period),1st dose of drug in OL period up to Week 192 (OL period) and 1st dose of drug in extension period up to Week 492 (extension period)
    Adverse event reporting additional description
    Safety population included all randomised subjects exposed to study medication, regardless of the amount of treatment administered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Double-Blind treatment period: Placebo
    Reporting group description
    		 Subjects received placebo matching to teriflunomide tablet orally QD for 96 weeks.

    Reporting group title
    Double-Blind treatment period: Teriflunomide
    Reporting group description
    		 Subjects received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <=95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.

    Reporting group title
    Open-Label treatment period: Placebo/Teriflunomide
    Reporting group description
    		 Subjects previously treated with placebo during the DB period received 1 teriflunomide tablet 3.5 mg (BW<=40 kg) or 7 mg teriflunomide (BW >40 kg) for first 8 weeks. After 8 weeks if predicted PK parameter was <= 95th percentile of adult range then subjects received 7 mg teriflunomide (BW<=40 kg) and 14 mg teriflunomide (BW>40 kg) in the OL period for 96 weeks (i.e., up to Week 192). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.

    Reporting group title
    Open-Label treatment period: Teriflunomide/Teriflunomide
    Reporting group description
    		 Subjects previously treated with Teriflunomide during DB period continued receiving Teriflunomide in the OL period for additional 96 weeks (i.e., up to Week 192).

    Reporting group title
    Extension period/Teriflunomide
    Reporting group description
    		 Subjects who were not adults when they completed the 192-week OL period were offered an optional additional extension period to receive 1 teriflunomide tablet 14 mg daily (or every other day if BW <40 kg) until they became adults or until they were able to switch to the commercial product, whichever came first.

    Serious adverse events
    		 Double-Blind treatment period: Placebo Double-Blind treatment period: Teriflunomide Open-Label treatment period: Placebo/Teriflunomide Open-Label treatment period: Teriflunomide/Teriflunomide Extension period/Teriflunomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 57 (10.53%)
    12 / 109 (11.01%)
    15 / 52 (28.85%)
    14 / 100 (14.00%)
    8 / 27 (29.63%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait Disturbance
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression Suicidal
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adjustment Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Affective Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatic Symptom Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
    1 / 52 (1.92%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Nerve Injury
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Familial Mediterranean Fever
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 109 (1.83%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Pseudo Relapse
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial Seizures
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden Hearing Loss
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatic Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food Poisoning
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug Eruption
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronavirus Infection
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Sinusitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis Viral
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-Oophoritis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complicated Appendicitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Double-Blind treatment period: Placebo Double-Blind treatment period: Teriflunomide Open-Label treatment period: Placebo/Teriflunomide Open-Label treatment period: Teriflunomide/Teriflunomide Extension period/Teriflunomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 57 (73.68%)
    89 / 109 (81.65%)
    40 / 52 (76.92%)
    72 / 100 (72.00%)
    18 / 27 (66.67%)
    Vascular disorders
    Orthostatic Hypotension
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    0
    5
    1
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    2
    0
    Asthenia
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    3
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 109 (3.67%)
    4 / 52 (7.69%)
    4 / 100 (4.00%)
    0 / 27 (0.00%)
         occurrences all number
    5
    6
    7
    4
    0
    Pyrexia
         subjects affected / exposed
    2 / 57 (3.51%)
    5 / 109 (4.59%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    8
    0
    3
    2
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    4
    0
    2
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 109 (0.92%)
    1 / 52 (1.92%)
    2 / 100 (2.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    4
    5
    1
    Menstrual Disorder
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis Allergic
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Respiratory Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    7 / 109 (6.42%)
    2 / 52 (3.85%)
    7 / 100 (7.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    8
    2
    9
    1
    Nasal Congestion
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Cough
         subjects affected / exposed
    3 / 57 (5.26%)
    5 / 109 (4.59%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    6
    2
    1
    1
    Epistaxis
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 109 (1.83%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    4
    0
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 109 (0.92%)
    1 / 52 (1.92%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    3
    1
    0
    Depression
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
    4 / 52 (7.69%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    4
    2
    0
    Anxiety
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 109 (3.67%)
    1 / 52 (1.92%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    6
    1
    3
    0
    Mixed Anxiety And Depressive Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 109 (1.83%)
    6 / 52 (11.54%)
    3 / 100 (3.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    3
    6
    3
    2
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 57 (1.75%)
    5 / 109 (4.59%)
    2 / 52 (3.85%)
    5 / 100 (5.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    8
    5
    9
    7
    Weight Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    4
    0
    3
    0
    Weight Decreased
         subjects affected / exposed
    3 / 57 (5.26%)
    6 / 109 (5.50%)
    2 / 52 (3.85%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    7
    2
    5
    0
    Protein Urine Present
         subjects affected / exposed
    1 / 57 (1.75%)
    4 / 109 (3.67%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    5
    2
    1
    0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    6
    1
    0
    2
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    1 / 52 (1.92%)
    2 / 100 (2.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    5
    4
    6
    5
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood Albumin Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood Uric Acid Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Electrocardiogram St-T Segment Abnormal
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    White Blood Cells Urine Positive
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Neutrophil/Lymphocyte Ratio Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    0
    1
    Neutrophil Percentage Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Monocyte Percentage Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Monocyte Count Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    1 / 52 (1.92%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    1
    4
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Glomerular Filtration Rate Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Haematocrit Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    1
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
    1 / 52 (1.92%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    4
    1
    1
    0
    Fall
         subjects affected / exposed
    4 / 57 (7.02%)
    6 / 109 (5.50%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    5
    8
    3
    1
    0
    Ligament Sprain
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    1 / 52 (1.92%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    3
    2
    0
    Accidental Overdose
         subjects affected / exposed
    4 / 57 (7.02%)
    5 / 109 (4.59%)
    2 / 52 (3.85%)
    10 / 100 (10.00%)
    3 / 27 (11.11%)
         occurrences all number
    7
    5
    2
    12
    3
    Thermal Burn
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Hip Fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    3
    0
    2
    1
    Sinus Tachycardia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Sinus Bradycardia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    2 / 57 (3.51%)
    11 / 109 (10.09%)
    1 / 52 (1.92%)
    4 / 100 (4.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    19
    1
    7
    0
    Hypoaesthesia
         subjects affected / exposed
    3 / 57 (5.26%)
    6 / 109 (5.50%)
    3 / 52 (5.77%)
    3 / 100 (3.00%)
    1 / 27 (3.70%)
         occurrences all number
    5
    7
    4
    4
    1
    Headache
         subjects affected / exposed
    13 / 57 (22.81%)
    18 / 109 (16.51%)
    7 / 52 (13.46%)
    14 / 100 (14.00%)
    1 / 27 (3.70%)
         occurrences all number
    18
    30
    22
    28
    1
    Disturbance In Attention
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 57 (7.02%)
    9 / 109 (8.26%)
    6 / 52 (11.54%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    5
    9
    12
    3
    0
    Presyncope
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    Tremor
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    2
    1
    1
    Syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    3 / 52 (5.77%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    6 / 100 (6.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    6
    0
    Neutropenia
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    Lymphopenia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 109 (2.75%)
    1 / 52 (1.92%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    3
    1
    1
    0
    Tinnitus
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
    1 / 52 (1.92%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    1
    0
    0
    Eye disorders
    Visual Impairment
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    2
    1
    0
    Vision Blurred
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    3
    0
    3
    0
    Eye Pain
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 109 (3.67%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    8
    4
    0
    3
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 57 (1.75%)
    11 / 109 (10.09%)
    2 / 52 (3.85%)
    8 / 100 (8.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    13
    2
    11
    0
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 57 (3.51%)
    6 / 109 (5.50%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    9
    0
    4
    0
    Aphthous Ulcer
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    2
    1
    0
    Diarrhoea
         subjects affected / exposed
    4 / 57 (7.02%)
    8 / 109 (7.34%)
    6 / 52 (11.54%)
    7 / 100 (7.00%)
    1 / 27 (3.70%)
         occurrences all number
    4
    9
    8
    9
    1
    Constipation
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 109 (0.92%)
    2 / 52 (3.85%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    2
    3
    0
    Mouth Ulceration
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
    2 / 52 (3.85%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    4
    3
    0
    Nausea
         subjects affected / exposed
    4 / 57 (7.02%)
    10 / 109 (9.17%)
    3 / 52 (5.77%)
    4 / 100 (4.00%)
    0 / 27 (0.00%)
         occurrences all number
    5
    12
    3
    4
    0
    Vomiting
         subjects affected / exposed
    5 / 57 (8.77%)
    6 / 109 (5.50%)
    2 / 52 (3.85%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    5
    7
    2
    2
    0
    Gastrointestinal Disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 109 (1.83%)
    0 / 52 (0.00%)
    2 / 100 (2.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    0
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 57 (12.28%)
    24 / 109 (22.02%)
    9 / 52 (17.31%)
    10 / 100 (10.00%)
    1 / 27 (3.70%)
         occurrences all number
    7
    26
    10
    10
    1
    Dry Skin
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Acne
         subjects affected / exposed
    4 / 57 (7.02%)
    5 / 109 (4.59%)
    0 / 52 (0.00%)
    4 / 100 (4.00%)
    0 / 27 (0.00%)
         occurrences all number
    4
    5
    0
    5
    0
    Eczema
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    4
    0
    Rash
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
    2 / 52 (3.85%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    4
    2
    2
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    2
    1
    0
    Micturition Urgency
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 109 (1.83%)
    5 / 52 (9.62%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    6
    0
    0
    Endocrine disorders
    Autoimmune Thyroiditis
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 57 (5.26%)
    5 / 109 (4.59%)
    2 / 52 (3.85%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    7
    5
    2
    1
    0
    Muscle Spasms
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    2
    0
    0
    Back Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    5 / 109 (4.59%)
    2 / 52 (3.85%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    6
    3
    5
    0
    Muscular Weakness
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    3 / 52 (5.77%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    3
    0
    0
    Pain In Extremity
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 109 (2.75%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    3
    0
    4
    0
    Infections and infestations
    Acute Sinusitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 57 (1.75%)
    5 / 109 (4.59%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    5
    2
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 109 (2.75%)
    2 / 52 (3.85%)
    5 / 100 (5.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    3
    2
    6
    1
    Influenza
         subjects affected / exposed
    4 / 57 (7.02%)
    10 / 109 (9.17%)
    5 / 52 (9.62%)
    5 / 100 (5.00%)
    2 / 27 (7.41%)
         occurrences all number
    4
    16
    6
    6
    3
    Nasopharyngitis
         subjects affected / exposed
    5 / 57 (8.77%)
    28 / 109 (25.69%)
    8 / 52 (15.38%)
    20 / 100 (20.00%)
    4 / 27 (14.81%)
         occurrences all number
    6
    50
    13
    37
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 57 (10.53%)
    24 / 109 (22.02%)
    7 / 52 (13.46%)
    22 / 100 (22.00%)
    6 / 27 (22.22%)
         occurrences all number
    23
    66
    32
    59
    12
    Tracheobronchitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Tracheitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    2 / 52 (3.85%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Tonsillitis
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
    2 / 52 (3.85%)
    4 / 100 (4.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    4
    4
    5
    0
    Tinea Versicolour
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
    2 / 52 (3.85%)
    2 / 100 (2.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    4
    3
    2
    0
    Rhinitis
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
    2 / 52 (3.85%)
    6 / 100 (6.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    8
    4
    7
    1
    Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
    0 / 52 (0.00%)
    1 / 100 (1.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    7
    0
    1
    0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 109 (0.92%)
    1 / 52 (1.92%)
    5 / 100 (5.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    5
    1
    Pharyngitis
         subjects affected / exposed
    1 / 57 (1.75%)
    7 / 109 (6.42%)
    1 / 52 (1.92%)
    4 / 100 (4.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    8
    2
    8
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
    2 / 52 (3.85%)
    5 / 100 (5.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    2
    5
    0
    Pulpitis Dental
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    0
    0
    1
    Covid-19
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    0
    0
    0
    3
    Root Canal Infection
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
    0 / 52 (0.00%)
    3 / 100 (3.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    3
    0
    3
    1
    Vitamin D Deficiency
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 109 (2.75%)
    1 / 52 (1.92%)
    4 / 100 (4.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    4
    1
    4
    0
    Iron Deficiency
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
    0 / 52 (0.00%)
    0 / 100 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2013
    Following changes were made: 1 MRI added at Weeks 24, 48 and 96 to strengthen MRI data; 1 MRI added at Week 36 in case of at least 5 new/enlarged T2 lesions; change in volume of T2 lesions, change in volume of T1 hypointense lesions, number of new T1 hypointense lesions, and brain atrophy were added and grouped as MRI endpoints; addition of immunoglobulin (IgG, IgM, and IgA) measurements at Baseline and every 24 weeks, aimed to provide additional information on a potential, although not expected, effect of teriflunomide on the immune system in this age group; poisson regression model changed in negative binomial model for the analysis of the number of new or enlarged T2-lesions and the number of T1 Gd-enhancing lesions per MRI scan. Reduced the impact of potential outliers, ordinal logistic regression model including treatment group, region, pubertal status, and age were also used to analyse these endpoints. The Poisson regression model with a robust error variance was to be used in sensitivity analyses.
    26 Jun 2014
    Following changes were made: Extension of the open-label period up to 192 weeks after randomisation; one MRI timepoint added at Week 72; addition of a criterion for switch into open-label period taking this additional MRI scan into account as follows: at least 5 new/enlarged T2 lesions on each of the 2 consecutive MRI scans of Week 48 and Week 72; change in exclusion criteria: the required minimum washout period duration for previous multiple sclerosis (MS) treatment was modified; addition of exclusion criteria: previous treatment with alemtuzumab; addition of a note about the content of teriflunomide tablets (lactose) and that therefore, investigators were to consider whether history of lactose intolerance could affect treatment tolerability; addition of a note about contraception and the association of local additional requirements (United Kingdom) to be followed, e.g., spermicidal foam/gel/film/cream/suppository, as per medicines and healthcare products regulatory agency rules; addition of endpoints: proportion of subjects free of new or enlarged MRI T2-lesions at Weeks 48 and 96. It was specified that the main MRI endpoints were the number of new/newly enlarged T2 lesions and the number of T1 Gd-enhancing T1 lesions; proportion of disease-free subjects as an exploratory endpoint; addition of text to introduce the rationale for placebo-controlled design; addition of endocrine function evaluation consisting of measurement of thyroid stimulating hormone (TSH) every 24 weeks and at end of treatment (EOT); addition of text to specify that local anesthetic was to be offered for blood draws to minimise pain and discomfort; correction of text: Pre-defined adverse events and laboratory abnormalities for specific reporting to restore the instructions that were included in the initial protocol but had been inadvertently taken out in Amended protocol 1.
    10 Dec 2020
    Following changes were done: Added specifications about weight and electrocardiogram during remote visits and reference to appendix G. Added text in case of emergency and reference to appendix G. Added IMP return specification and reference to appendix G. Added text in case of emergency and reference to appendix G. Added text in case of missing assessment and reference to Appendix G. Added cross references to sections. Added text on permanently discontinuation for subjects close to the end of treatment may be unable to continue their final treatment as scheduled. Added monitoring details, techniques, and source data verification. Added summaries of the 3 memos to detail the procedures set up in case of emergency.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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