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    Clinical Trial Results:
    A Multi-center, Randomized, Parallel-group, Rater-blinded Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis Plus a Long Term Extension Period

    Summary
    EudraCT number
    		 2008-006226-34
    Trial protocol
    		 ES   DE   HU   CZ   IT   GR   FR   BE   GB  
    Global end of trial date
    13 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 May 2016
    First version publication date
    25 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC10891
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00883337
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study Name: TENERE
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette Chilly, Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effectiveness of 2 doses of teriflunomide in comparison to interferon-beta 1 a, evaluated by the time to failure, with failure being defined as either relapse or permanent study treatment discontinuation for any cause whichever comes first.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial, the subject is participating in, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Apr 2009
    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
    Poland: 62
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 55
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Tunisia: 1
    Worldwide total number of subjects
    324
    EEA total number of subjects
    301
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    323
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment initiated in April 2009 was completed in July 2010. A total of 369 subjects were screened at 54 sites in 13 countries. The common end date of core treatment period was 14 September 2011 (maximum treatment duration of 115 weeks). The end date of extension was 13 May 2015 (maximum treatment duration of 197 weeks).

    Pre-assignment
    Screening details
    		 Randomization was stratified by country and baseline disability (Expanded Disability Status Scale [EDSS] score ≤3.5 or >3.5). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS] in a 1:1:1 ratio after confirmation of the selection criteria. 324 subjects were randomized at 53 sites.

    Period 1
    Period 1 title
    Core Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Teriflunomide 7 mg
    Arm description
    		 Teriflunomide 7 mg once daily for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide orally as a single dose in the morning of each day with water and may be taken with or without food.

    Arm title
    		 Teriflunomide 14 mg
    Arm description
    		 Teriflunomide 14 mg once daily for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide orally as a single dose in the morning of each day with water and may be taken with or without food. One Subject received teriflunomide 7 mg instead of teriflunomide 14 mg.

    Arm title
    		 Interferon beta-1-a (IFN-β-1a)
    Arm description
    		 IFN-β-1a three times a week for 48 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Interferon beta-1a
    Investigational medicinal product code
    Other name
    Rebif®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IFN-β-1a subcutaneous (SC) injection at the same time on the same three days in the late afternoon or evening. Three subjects refused treatment with Rebif®.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: As per the trial design only assessor was blinded in the study.
    Number of subjects in period 1
    		Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a)
    Started
    109
    111
    104
    Treated
    109
    111
    101
    Completed
    89
    89
    71
    Not completed
    20
    22
    33
         Other than specified above
    -
    1
    1
         Adverse event
    9
    12
    22
         Poor compliance to protocol
    -
    -
    1
         Lost to follow-up
    1
    1
    -
         Wish to be pregnant
    1
    2
    1
         Lack of efficacy
    7
    4
    2
         Withdrawal by subject
    2
    2
    6
    Period 2
    Period 2 title
    Extension Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [2]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Teriflunomide 7 mg / 14 mg
    Arm description
    		 Subjects received teriflunomide 7 mg once daily in core treatment period and teriflunomide 14 mg once daily in extension treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide orally as a single dose in the morning of each day with water and may be taken with or without food.

    Arm title
    		 Teriflunomide 14 mg / 14 mg
    Arm description
    		 Subjects received teriflunomide 14 mg once daily in core treatment period and teriflunomide 14 mg once daily in extension treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide orally as a single dose in the morning of each day with water and may be taken with or without food.

    Arm title
    		 IFN-β-1a / Teriflunomide 14 mg
    Arm description
    		 Subjects received IFN-β-1a three times a week in core treatment period and teriflunomide 14 mg once daily in extension treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide orally as a single dose in the morning of each day with water and may be taken with or without food.

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: As per the trial design only assessor was blinded in the study.
    Number of subjects in period 2 [3]
    		Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg IFN-β-1a / Teriflunomide 14 mg
    Started
    89
    89
    59
    Completed
    61
    66
    40
    Not completed
    28
    23
    19
         Other than specified above
    10
    9
    5
         Adverse event
    8
    5
    5
         Poor compliance to protocol
    1
    1
    1
         Lost to follow-up
    1
    -
    -
         Lack of efficacy
    8
    8
    8
    Notes
    [3] - 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: 12 subjects completed the core period but didn't enter the extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Teriflunomide 7 mg
    Reporting group description
    		 Teriflunomide 7 mg once daily for 48 weeks.

    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 Teriflunomide 14 mg once daily for 48 weeks.

    Reporting group title
    Interferon beta-1-a (IFN-β-1a)
    Reporting group description
    		 IFN-β-1a three times a week for 48 weeks.

    Reporting group values
    		 Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a) Total
    Number of subjects
    		 109 111 104 324
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.5 ( 9.2 ) 36.8 ( 10.3 ) 37 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 70 78 71 219
        Male
    		 39 33 33 105
    Region of Enrollment
    Due the small sample size in some countries, the countries were pooled as follows: - North America: Canada; - Eastern Europe: Czech Republic, Greece, Hungary and Poland; - Western Europe: Belgium, France, Germany, Italy, Spain, Switzerland and United Kingdom; subject in Tunisia was included in the Western Europe group.
    Units: Subjects
        North America
    		 8 6 7 21
        Eastern Europe
    		 39 41 35 115
        Western Europe
    		 62 64 62 188
    Multiple Sclerosis (MS) subtype
    Units: Subjects
        Relapsing Remitting
    		 109 108 104 321
        Secondary Progressive
    		 0 1 0 1
        Progressive Relapsing
    		 0 2 0 2
    Baseline EDSS score
    EDSS is an ordinal scale in half-point increments that qualifies disability in subjects with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brain-stem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS).
    Units: Subjects
        ≤3.5
    		 96 95 93 284
        >3.5
    		 13 16 11 40
    Time since first diagnosis of MS
    Units: years
        arithmetic mean (standard deviation)
    		 3.72 ( 5.19 ) 3.68 ( 6.24 ) 3.82 ( 5.69 ) -
    Time since most recent MS relapse onset
    The information was not available for one subject in the Teriflunomide 14 mg group.
    Units: months
        arithmetic mean (standard deviation)
    		 9 ( 13.96 ) 7.9 ( 10.34 ) 9.79 ( 10.72 ) -
    Number of MS relapses within the past year
    Units: relapses
        median (full range (min-max))
    		 1 (0 to 3) 1 (0 to 4) 1 (0 to 5) -
    Number of MS relapses within the past 2 years
    Units: relapses
        median (full range (min-max))
    		 2 (0 to 4) 2 (0 to 4) 2 (0 to 6) -

    End points

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    End points reporting groups
    Reporting group title
    Teriflunomide 7 mg
    Reporting group description
    		 Teriflunomide 7 mg once daily for 48 weeks.

    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 Teriflunomide 14 mg once daily for 48 weeks.

    Reporting group title
    Interferon beta-1-a (IFN-β-1a)
    Reporting group description
    		 IFN-β-1a three times a week for 48 weeks.
    Reporting group title
    Teriflunomide 7 mg / 14 mg
    Reporting group description
    		 Subjects received teriflunomide 7 mg once daily in core treatment period and teriflunomide 14 mg once daily in extension treatment period.

    Reporting group title
    Teriflunomide 14 mg / 14 mg
    Reporting group description
    		 Subjects received teriflunomide 14 mg once daily in core treatment period and teriflunomide 14 mg once daily in extension treatment period.

    Reporting group title
    IFN-β-1a / Teriflunomide 14 mg
    Reporting group description
    		 Subjects received IFN-β-1a three times a week in core treatment period and teriflunomide 14 mg once daily in extension treatment period.

    Subject analysis set title
    Teriflunomide 7 mg / 14 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received teriflunomide 7 mg once daily in core treatment period and teriflunomide 14 mg once daily in extension treatment period.

    Subject analysis set title
    Teriflunomide 7 mg / 14 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received teriflunomide 7 mg once daily in core treatment period and teriflunomide 14 mg once daily in extension treatment period.

    Primary: Core Treatment Period: Overview of Failures

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    End point title
    		 Core Treatment Period: Overview of Failures [1]
    End point description
    Failure was defined as the first occurrence of confirmed relapse or permanent treatment discontinuation (for any cause) which ever came first. If no events occurred, the subject was considered free of failure. Each episode of relapse appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever was to be confirmed by an increase in EDSS score or Functional System scores. Intent-to-treat population: all randomized subjects. Subjects were considered in the treatment group to which they were randomized regardless of the drug they actually received.
    End point type
    Primary
    End point timeframe
    Core treatment period between 48 and 118 weeks depending on when the subject was enrolled
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As data is descriptive in nature, no statistical analysis is performed.
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a)
    Number of subjects analysed
    109
    111
    104
    Units: Subjects
        Failure
    53
    42
    44
        Free of Failure
    56
    69
    60
    No statistical analyses for this end point

    Primary: Core Treatment Period: Time to Failure: KaplanMeier Estimates of the Rate of Failure at Timepoints

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    End point title
    		 Core Treatment Period: Time to Failure: KaplanMeier Estimates of the Rate of Failure at Timepoints
    End point description
    Probability of disability progression at 24, 48 and 96 weeks was estimated using Kaplan-Meier method on the time to failure defined as the time from randomization to failure. Subjects free of failure were censored at the date of last treatment. Kaplan-Meier method consists in computing probabilities of non-occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t. Probability of event at time t is 1 minus the probability of being event-free for the amount of time t. ITT population.
    End point type
    Primary
    End point timeframe
    Core treatment period between 48 and 118 weeks depending on when the subject was enrolled
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a)
    Number of subjects analysed
    109
    111
    104
    Units: Percent probability
    number (confidence interval 95%)
        Probability of failure at 24 weeks
    25.7 (17.5 to 33.9)
    24.3 (16.3 to 32.3)
    29.8 (21 to 38.6)
        Probability of failure at 48 weeks
    35.8 (26.8 to 44.8)
    33.3 (24.6 to 42.1)
    36.5 (27.3 to 45.8)
        Probability of failure at 96 weeks
    58.8 (46.1 to 71.4)
    41.1 (30.9 to 51.4)
    44.4 (34.3 to 54.4)
    Statistical analysis title
    		 Teriflunomide 14 mg vs IFNβ-1-a
    Statistical analysis description
    The study was sized to detect a difference between teriflunomide and Rebif groups in the time to failure at a significance level of 0.025 with a power of 81%. Null hypothesis: H1: No difference between teriflunomide 14 mg and Rebif H2: No difference between teriflunomide 7 mg and Rebif
    Comparison groups
    Teriflunomide 14 mg v Interferon beta-1-a (IFN-β-1a)
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.5953 [3]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Hochberg testing procedure: -a-priori threshold for statistical significance ≤0.05 for the largest p-value of the 2 pair-wise comparisons. -a-priori threshold for statistical significance ≤0.025 for the other p-value, if the largest p-value >0.05.
    [3] - Two-sided Log Rank test with the region of enrollment and baseline EDSS stratum as stratification factors.
    Statistical analysis title
    		 Teriflunomide 7 mg vs IFNβ-1-a
    Statistical analysis description
    Null hypothesis: -H1: No difference between teriflunomide 14 mg and Rebif -H2: No difference between teriflunomide 7 mg and Rebif
    Comparison groups
    Teriflunomide 7 mg v Interferon beta-1-a (IFN-β-1a)
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.519 [5]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - Hochberg testing procedure: -a-priori threshold for statistical significance ≤0.05 for the largest p-value of the 2 pair-wise comparisons. -a-priori threshold for statistical significance ≤0.025 for the other p-value, if the largest p-value >0.05.
    [5] - Two-sided Log Rank test with the region of enrollment and baseline EDSS stratum as stratification factors.

    Secondary: Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates

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    End point title
    		 Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates
    End point description
    ARR is obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of the treatment durations. To account for the different treatment durations among subjects, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and baseline EDSS stratum as covariates). ITT population.
    End point type
    Secondary
    End point timeframe
    Core treatment period between 48 and 118 weeks depending on when the subject was enrolled.
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a)
    Number of subjects analysed
    109
    111
    104
    Units: Relapses per year
        number (confidence interval 95%)
    0.41 (0.265 to 0.636)
    0.259 (0.153 to 0.438)
    0.216 (0.113 to 0.415)
    No statistical analyses for this end point

    Secondary: Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score

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    End point title
    		 Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score
    End point description
    FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in subjects with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (before randomization) and 48 weeks
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a)
    Number of subjects analysed
    109
    111
    104
    Units: Units on a scale
        least squares mean (standard error)
    0.97 ( 2.96 )
    4.1 ( 3.03 )
    9.1 ( 3.21 )
    No statistical analyses for this end point

    Secondary: Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores

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    End point title
    		 Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores
    End point description
    TSQM version 1.4 is an instrument to assess subjects' satisfaction with medication. It consists of 13 questions that cover three dimensions (effectiveness, side effects and convenience) plus a global satisfaction question. Four scores ranging from 0 to 100 (extremely satisfied) are obtained. Least-square means were estimated using a MMRM on TSQM score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction as factors). ITT population.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a)
    Number of subjects analysed
    109
    111
    104
    Units: Units on a scale
    least squares mean (standard error)
        Effectivness score
    67.25 ( 2.7 )
    63.13 ( 2.75 )
    59.3 ( 2.97 )
        Side effects score
    95.29 ( 2.31 )
    93.15 ( 2.34 )
    71.38 ( 2.5 )
        Convenience score
    88.3 ( 1.97 )
    89.85 ( 1.98 )
    61.9 ( 2.11 )
        Global satisfaction score
    68.29 ( 2.77 )
    68.82 ( 2.78 )
    60.98 ( 2.94 )
    No statistical analyses for this end point

    Secondary: Core Treatment Period: Overview of Adverse Events [AEs]

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    End point title
    		 Core Treatment Period: Overview of Adverse Events [AEs] [6]
    End point description
    AEs were any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the subject during the study. Safety population: all randomized and treated subjects. Subjects were considered according to the drug actually received. The subject randomized to teriflunomide 14 mg group who received teriflunomide 7 mg was analyzed in the teriflunomide 7 mg group.
    End point type
    Secondary
    End point timeframe
    From first study drug intake up to 112 days after last intake in the core treatment period or up to first intake in the extension treatment period, whichever occurred first.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The was data provided for core treatment period only.
    End point values
    		 Teriflunomide 14 mg Interferon beta-1-a (IFN-β-1a) Teriflunomide 7 mg / 14 mg
    Number of subjects analysed
    110
    101
    110
    Units: subjects
        Any AE
    102
    97
    103
        Any serious AE
    6
    7
    12
        Any AE leading to death
    0
    0
    0
        Any AE leading to treatment discontinuation
    12
    22
    9
    No statistical analyses for this end point

    Secondary: Extension Treatment Period: Overview of AEs

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    End point title
    		 Extension Treatment Period: Overview of AEs
    End point description
    AEs were any unfavourable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the subject during the study. Safety population: subjects were considered in the treatment group to which they were randomized regardless of the drug they actually received.
    End point type
    Secondary
    End point timeframe
    From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period
    End point values
    		 Teriflunomide 14 mg / 14 mg IFN-β-1a / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg
    Number of subjects analysed
    88
    59
    90
    Units: subjects
        Any AE
    76
    48
    83
        Any serious AE
    13
    12
    9
        Any AE leading to death
    0
    0
    0
        Any AE leading to treatment discontinuation
    6
    5
    8
    No statistical analyses for this end point

    Secondary: Extension Treatment Period: ARR Poisson Regression Estimates

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    End point title
    		 Extension Treatment Period: ARR Poisson Regression Estimates
    End point description
    ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of the standardized treatment durations. To account for the different treatment durations among subjects, a Poisson Regression Model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and baseline EDSS stratum as covariates). ITT population.
    End point type
    Secondary
    End point timeframe
    Extension treatment period (Maximum: 197 weeks)
    End point values
    		 Teriflunomide 14 mg / 14 mg IFN-β-1a / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg
    Number of subjects analysed
    89
    59
    89
    Units: Relapses per year
        number (confidence interval 95%)
    0.193 (0.121 to 0.307)
    0.252 (0.145 to 0.438)
    0.236 (0.154 to 0.362)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 197) regardless of seriousness or relationship to Investigational Medicinal Product (IMP).
    Adverse event reporting additional description
    The analysis was performed on the safety population as previously defined. Reported adverse events are treatment emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (up to 28 days after the last intake of IMP in the extension study treatment period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Core Treatment: Teriflunomide 7 mg
    Reporting group description
    		 Teriflunomide 7 mg once daily (mean exposure of 456.62 days).

    Reporting group title
    Core Treatment:Teriflunomide 14 mg
    Reporting group description
    		 Teriflunomide 14 mg once daily (mean exposure of 434.43 days).

    Reporting group title
    Core Treatment: IFN-β-1a
    Reporting group description
    		 Interferon β-1a 3 times a week (mean exposure of 405.18 days).

    Reporting group title
    Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a)
    Reporting group description
    		 Teriflunomide 14 mg once daily in extended treatment period after Interferon β-1a 3 times a week in core treatment period (mean exposure of 1000.03 days).

    Reporting group title
    Extended Treatment: Teriflunomide 14 mg (After 7 mg)
    Reporting group description
    		 Teriflunomide 14 mg once daily in extended treatment period after 7 mg in the core treatment period (mean exposure of 996.76 days).

    Reporting group title
    Extended Treatment: Teriflunomide 14 mg (After 14 mg)
    Reporting group description
    		 Teriflunomide 14 mg once daily in extended treatment period after 14 mg in core treatment period (mean exposure of 1015.32 days).

    Serious adverse events
    		 Core Treatment: Teriflunomide 7 mg Core Treatment:Teriflunomide 14 mg Core Treatment: IFN-β-1a Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a) Extended Treatment: Teriflunomide 14 mg (After 7 mg) Extended Treatment: Teriflunomide 14 mg (After 14 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 110 (10.91%)
    6 / 110 (5.45%)
    7 / 101 (6.93%)
    12 / 59 (20.34%)
    9 / 90 (10.00%)
    13 / 88 (14.77%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyosarcoma
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Varicose Vein
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous Stenosis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    1 / 101 (0.99%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait Disturbance
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Haemorrhage
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Polyp
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    1 / 101 (0.99%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal Septum Deviation
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide Attempt
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    3 / 110 (2.73%)
    1 / 110 (0.91%)
    1 / 101 (0.99%)
    0 / 59 (0.00%)
    2 / 90 (2.22%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm Fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    1 / 101 (0.99%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary Artery Disease
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal Tunnel Syndrome
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic Neuritis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye Oedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic Ischaemic Neuropathy
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Perforation
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's Disease
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    1 / 101 (0.99%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema Nodosum
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot Deformity
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    1 / 101 (0.99%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis Perforated
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Pyelonephritis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    1 / 101 (0.99%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis Bacterial
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    0 / 101 (0.00%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Core Treatment: Teriflunomide 7 mg Core Treatment:Teriflunomide 14 mg Core Treatment: IFN-β-1a Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a) Extended Treatment: Teriflunomide 14 mg (After 7 mg) Extended Treatment: Teriflunomide 14 mg (After 14 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 110 (77.27%)
    92 / 110 (83.64%)
    92 / 101 (91.09%)
    48 / 59 (81.36%)
    72 / 90 (80.00%)
    65 / 88 (73.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 110 (0.00%)
    5 / 110 (4.55%)
    4 / 101 (3.96%)
    7 / 59 (11.86%)
    7 / 90 (7.78%)
    9 / 88 (10.23%)
         occurrences all number
    0
    5
    4
    7
    7
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 110 (6.36%)
    6 / 110 (5.45%)
    5 / 101 (4.95%)
    2 / 59 (3.39%)
    4 / 90 (4.44%)
    4 / 88 (4.55%)
         occurrences all number
    7
    6
    5
    2
    4
    4
    Asthenia
         subjects affected / exposed
    3 / 110 (2.73%)
    1 / 110 (0.91%)
    9 / 101 (8.91%)
    3 / 59 (5.08%)
    0 / 90 (0.00%)
    2 / 88 (2.27%)
         occurrences all number
    3
    1
    9
    3
    0
    2
    Pyrexia
         subjects affected / exposed
    10 / 110 (9.09%)
    2 / 110 (1.82%)
    3 / 101 (2.97%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    1 / 88 (1.14%)
         occurrences all number
    10
    2
    3
    0
    1
    1
    Influenza Like Illness
         subjects affected / exposed
    4 / 110 (3.64%)
    4 / 110 (3.64%)
    49 / 101 (48.51%)
    6 / 59 (10.17%)
    2 / 90 (2.22%)
    0 / 88 (0.00%)
         occurrences all number
    4
    4
    49
    6
    2
    0
    Injection Site Erythema
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    10 / 101 (9.90%)
    0 / 59 (0.00%)
    0 / 90 (0.00%)
    0 / 88 (0.00%)
         occurrences all number
    0
    0
    10
    0
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 110 (2.73%)
    6 / 110 (5.45%)
    1 / 101 (0.99%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    2 / 88 (2.27%)
         occurrences all number
    3
    6
    1
    0
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 110 (6.36%)
    4 / 110 (3.64%)
    1 / 101 (0.99%)
    5 / 59 (8.47%)
    4 / 90 (4.44%)
    2 / 88 (2.27%)
         occurrences all number
    7
    4
    1
    5
    4
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 110 (6.36%)
    1 / 110 (0.91%)
    5 / 101 (4.95%)
    2 / 59 (3.39%)
    2 / 90 (2.22%)
    1 / 88 (1.14%)
         occurrences all number
    7
    1
    5
    2
    2
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    12 / 110 (10.91%)
    9 / 110 (8.18%)
    30 / 101 (29.70%)
    2 / 59 (3.39%)
    5 / 90 (5.56%)
    8 / 88 (9.09%)
         occurrences all number
    12
    9
    30
    2
    5
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 110 (5.45%)
    2 / 110 (1.82%)
    2 / 101 (1.98%)
    1 / 59 (1.69%)
    3 / 90 (3.33%)
    0 / 88 (0.00%)
         occurrences all number
    6
    2
    2
    1
    3
    0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    6 / 110 (5.45%)
    3 / 110 (2.73%)
    2 / 101 (1.98%)
    3 / 59 (5.08%)
    3 / 90 (3.33%)
    4 / 88 (4.55%)
         occurrences all number
    6
    3
    2
    3
    3
    4
    Dizziness
         subjects affected / exposed
    4 / 110 (3.64%)
    1 / 110 (0.91%)
    6 / 101 (5.94%)
    0 / 59 (0.00%)
    3 / 90 (3.33%)
    3 / 88 (3.41%)
         occurrences all number
    4
    1
    6
    0
    3
    3
    Headache
         subjects affected / exposed
    23 / 110 (20.91%)
    17 / 110 (15.45%)
    26 / 101 (25.74%)
    10 / 59 (16.95%)
    5 / 90 (5.56%)
    3 / 88 (3.41%)
         occurrences all number
    23
    17
    26
    10
    5
    3
    Sciatica
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 110 (0.00%)
    3 / 101 (2.97%)
    3 / 59 (5.08%)
    1 / 90 (1.11%)
    3 / 88 (3.41%)
         occurrences all number
    0
    0
    3
    3
    1
    3
    Paraesthesia
         subjects affected / exposed
    14 / 110 (12.73%)
    11 / 110 (10.00%)
    8 / 101 (7.92%)
    3 / 59 (5.08%)
    3 / 90 (3.33%)
    2 / 88 (2.27%)
         occurrences all number
    14
    11
    8
    3
    3
    2
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 110 (0.91%)
    2 / 110 (1.82%)
    4 / 101 (3.96%)
    3 / 59 (5.08%)
    1 / 90 (1.11%)
    2 / 88 (2.27%)
         occurrences all number
    1
    2
    4
    3
    1
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 110 (0.91%)
    2 / 101 (1.98%)
    5 / 59 (8.47%)
    5 / 90 (5.56%)
    6 / 88 (6.82%)
         occurrences all number
    1
    1
    2
    5
    5
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 110 (17.27%)
    17 / 110 (15.45%)
    9 / 101 (8.91%)
    8 / 59 (13.56%)
    10 / 90 (11.11%)
    15 / 88 (17.05%)
         occurrences all number
    19
    17
    9
    8
    10
    15
    Abdominal Pain
         subjects affected / exposed
    5 / 110 (4.55%)
    7 / 110 (6.36%)
    2 / 101 (1.98%)
    2 / 59 (3.39%)
    6 / 90 (6.67%)
    3 / 88 (3.41%)
         occurrences all number
    5
    7
    2
    2
    6
    3
    Abdominal Pain Upper
         subjects affected / exposed
    7 / 110 (6.36%)
    7 / 110 (6.36%)
    3 / 101 (2.97%)
    4 / 59 (6.78%)
    3 / 90 (3.33%)
    3 / 88 (3.41%)
         occurrences all number
    7
    7
    3
    4
    3
    3
    Nausea
         subjects affected / exposed
    10 / 110 (9.09%)
    10 / 110 (9.09%)
    4 / 101 (3.96%)
    1 / 59 (1.69%)
    0 / 90 (0.00%)
    2 / 88 (2.27%)
         occurrences all number
    10
    10
    4
    1
    0
    2
    Dyspepsia
         subjects affected / exposed
    4 / 110 (3.64%)
    4 / 110 (3.64%)
    0 / 101 (0.00%)
    3 / 59 (5.08%)
    3 / 90 (3.33%)
    1 / 88 (1.14%)
         occurrences all number
    4
    4
    0
    3
    3
    1
    Vomiting
         subjects affected / exposed
    6 / 110 (5.45%)
    9 / 110 (8.18%)
    4 / 101 (3.96%)
    1 / 59 (1.69%)
    2 / 90 (2.22%)
    1 / 88 (1.14%)
         occurrences all number
    6
    9
    4
    1
    2
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 110 (5.45%)
    22 / 110 (20.00%)
    1 / 101 (0.99%)
    4 / 59 (6.78%)
    4 / 90 (4.44%)
    1 / 88 (1.14%)
         occurrences all number
    6
    22
    1
    4
    4
    1
    Renal and urinary disorders
    Micturition Urgency
         subjects affected / exposed
    2 / 110 (1.82%)
    3 / 110 (2.73%)
    1 / 101 (0.99%)
    3 / 59 (5.08%)
    2 / 90 (2.22%)
    2 / 88 (2.27%)
         occurrences all number
    2
    3
    1
    3
    2
    2
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    10 / 110 (9.09%)
    11 / 110 (10.00%)
    7 / 101 (6.93%)
    5 / 59 (8.47%)
    5 / 90 (5.56%)
    6 / 88 (6.82%)
         occurrences all number
    10
    11
    7
    5
    5
    6
    Pain In Extremity
         subjects affected / exposed
    11 / 110 (10.00%)
    7 / 110 (6.36%)
    4 / 101 (3.96%)
    4 / 59 (6.78%)
    6 / 90 (6.67%)
    4 / 88 (4.55%)
         occurrences all number
    11
    7
    4
    4
    6
    4
    Arthralgia
         subjects affected / exposed
    6 / 110 (5.45%)
    7 / 110 (6.36%)
    4 / 101 (3.96%)
    4 / 59 (6.78%)
    6 / 90 (6.67%)
    3 / 88 (3.41%)
         occurrences all number
    6
    7
    4
    4
    6
    3
    Muscle Spasms
         subjects affected / exposed
    6 / 110 (5.45%)
    5 / 110 (4.55%)
    3 / 101 (2.97%)
    2 / 59 (3.39%)
    1 / 90 (1.11%)
    2 / 88 (2.27%)
         occurrences all number
    6
    5
    3
    2
    1
    2
    Myalgia
         subjects affected / exposed
    2 / 110 (1.82%)
    3 / 110 (2.73%)
    7 / 101 (6.93%)
    1 / 59 (1.69%)
    2 / 90 (2.22%)
    1 / 88 (1.14%)
         occurrences all number
    2
    3
    7
    1
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 110 (23.64%)
    24 / 110 (21.82%)
    17 / 101 (16.83%)
    3 / 59 (5.08%)
    11 / 90 (12.22%)
    9 / 88 (10.23%)
         occurrences all number
    26
    24
    17
    3
    11
    9
    Urinary Tract Infection
         subjects affected / exposed
    8 / 110 (7.27%)
    3 / 110 (2.73%)
    6 / 101 (5.94%)
    3 / 59 (5.08%)
    8 / 90 (8.89%)
    7 / 88 (7.95%)
         occurrences all number
    8
    3
    6
    3
    8
    7
    Bronchitis
         subjects affected / exposed
    8 / 110 (7.27%)
    4 / 110 (3.64%)
    2 / 101 (1.98%)
    4 / 59 (6.78%)
    4 / 90 (4.44%)
    5 / 88 (5.68%)
         occurrences all number
    8
    4
    2
    4
    4
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    8 / 110 (7.27%)
    11 / 110 (10.00%)
    9 / 101 (8.91%)
    3 / 59 (5.08%)
    2 / 90 (2.22%)
    5 / 88 (5.68%)
         occurrences all number
    8
    11
    9
    3
    2
    5
    Oral Herpes
         subjects affected / exposed
    9 / 110 (8.18%)
    0 / 110 (0.00%)
    2 / 101 (1.98%)
    0 / 59 (0.00%)
    1 / 90 (1.11%)
    4 / 88 (4.55%)
         occurrences all number
    9
    0
    2
    0
    1
    4
    Pharyngitis
         subjects affected / exposed
    8 / 110 (7.27%)
    1 / 110 (0.91%)
    3 / 101 (2.97%)
    5 / 59 (8.47%)
    4 / 90 (4.44%)
    4 / 88 (4.55%)
         occurrences all number
    8
    1
    3
    5
    4
    4
    Influenza
         subjects affected / exposed
    8 / 110 (7.27%)
    9 / 110 (8.18%)
    5 / 101 (4.95%)
    2 / 59 (3.39%)
    3 / 90 (3.33%)
    2 / 88 (2.27%)
         occurrences all number
    8
    9
    5
    2
    3
    2
    Ear Infection
         subjects affected / exposed
    3 / 110 (2.73%)
    2 / 110 (1.82%)
    2 / 101 (1.98%)
    3 / 59 (5.08%)
    0 / 90 (0.00%)
    1 / 88 (1.14%)
         occurrences all number
    3
    2
    2
    3
    0
    1
    Gastroenteritis
         subjects affected / exposed
    5 / 110 (4.55%)
    6 / 110 (5.45%)
    3 / 101 (2.97%)
    1 / 59 (1.69%)
    7 / 90 (7.78%)
    1 / 88 (1.14%)
         occurrences all number
    5
    6
    3
    1
    7
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2011
    Following changes were made: •Extension part of the study was elaborated, which was offered to all subjects randomized in EFC10891/TENERE and completed the treatment period - regardless of study arm (teriflunomide or interferon-beta 1a). This extension was an open-label study with all subjects treated with teriflunomide 14 mg/day. The extension was planned to last 48 weeks. •Teriflunomide elimination (washout) period was shortened from 16 weeks to 4 weeks to allow subjects to terminate treatment more rapidly. •Concomitant medications were modified, which could interfere with the study based on the updated drug interactions data (CYP2C9 substrate and CYP inducers). •Peripheral neuropathy confirmed by electrophysiological tests was added as an alert term. •Frequency of sample collection was reduced for PK based on available data of teriflunomide. •Clarification regarding reporting of AEs was required from signature of informed consent. •Rebif overdose, accountability and compliance, disposition of used syringes/cartridges, and other editorial corrections related to the IMP, were re-defined. •Clarification and corrected some inconsistencies throughout the protocol regarding neutropenia.
    12 Jul 2012
    • Extended the current extension period of the TENERE study up to when teriflunomide was commercially available in the country. • Modified the concomitant treatments based on the updated drug interactions data.
    28 Jan 2013
    •Reduction of scheduled study visits and visit contents for subjects completed a minimum 18 months/72 weeks in extension phase. •Clinical visits were performed every 24 weeks up to the end of treatment, and included adverse event reporting; recording of concomitant medication, vital signs, physical examination; dispense study drugs: accountability/compliance; EDSS /Functional System (FS); clinical laboratory only at EOT visit. •Central lab services would not be utilized. Lab tests were performed on local basis for all subjects. •Clarification that subjects continued on teriflunomide by obtaining it commercially after ending in this extension study, accelerated elimination procedure and follow-up visits were not required. •Updated on the PK handling procedure and sampling time. •New information regarding potential drug interactions •Dosage reduction of activated charcoal for accelerated elimination procedure (reduced from 50g 4 times daily for 11 days to 50g twice daily for 11 days).
    09 May 2013
    •Reduction of scheduled study visits and visit contents for subjects completed a minimum 72 weeks in extension phase. •Clinical visits was performed every 24 weeks up to the end of treatment, and included adverse event reporting; recording of concomitant medication, vital signs, physical examination; dispense study drugs: accountability/compliance; EDSS / FS; clinical laboratory only at EOT visit. •Central lab services was not be utilized except for post-accelerated elimination PK samples. Lab tests was performed on local basis for all subjects. •Clarification that subjects continued on teriflunomide by obtaining it commercially after ending in this extension study, accelerated elimination procedure and follow-up visits were not required. •Updated the PK handling procedure and sampling time. •New information regarding potential drug interactions. •Dosage reduction of activated charcoal for accelerated elimination procedure (reduced from 50g 4 times daily for 11 days to 50g twice daily for 11 days).

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24126064
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