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    Clinical Trial Results:
    Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Superiority Study to Compare the Efficacy and Safety of Ponesimod to Teriflunomide in Subjects With Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    		 2012-000540-10
    Trial protocol
    		 DE   FR   PL   LV   SE   CZ   LT   HU   FI   PT   ES   HR   GR  
    Global end of trial date
    16 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 May 2020
    First version publication date
    29 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-058B301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02425644
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.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
    16 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to determine whether ponesimod is more efficacious than teriflunomide in terms of reducing relapses in subjects with relapsing multiple sclerosis (RMS).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices (GCP) and applicable regulatory requirements. Safety was evaluated based on the following assessments: Adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, virus serology, serum, and urine pregnancy tests, urinalysis), 12-lead Electrocardiogram (ECG), blood pressure, pulse rate, body temperature, spirometry, diffusing capacity of the lungs measured using carbon monoxide (DLCO) tests (from the substudy), chest X-ray, tuberculosis test (QuantiFERON-TB-Gold), ophthalmologic assessments including ophthalmological exam and optical coherence tomography (OCT), weight, height, physical examination, dermatological examination, locally reviewed magnetic resonance imaging (MRI) for safety (non-multiple sclerosis [MS] central nervous system [CNS] pathology), and the Columbia-Suicide Severity Rating Scale (electronic self-rated version) (eC-SSRS) questionnaire.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 2015
    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
    Bulgaria: 45
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 3
    Country: Number of subjects enrolled
    Belarus: 45
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Czech Republic: 101
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Spain: 73
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Georgia: 41
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Croatia: 34
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Latvia: 15
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Poland: 151
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 227
    Country: Number of subjects enrolled
    Serbia: 33
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 123
    Country: Number of subjects enrolled
    United States: 39
    Worldwide total number of subjects
    1133
    EEA total number of subjects
    573
    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)
    1133
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1468 subjects screened. Among them, 1133 subjects were randomized in a 1:1 ratio to receive ponesimod 20 milligrams (mg) or teriflunomide 14 mg.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ponesimod 20 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ponesimod 20 mg (Maintenance)
    Investigational medicinal product code
    Other name
    JNJ-67896153, ACT-128800
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 20 mg ponesimod over-encapsulated tablet once daily during maintenance phase.

    Investigational medicinal product name
    Ponesimod 2 to 10 mg (Uptitration)
    Investigational medicinal product code
    Other name
    JNJ-67896153, ACT-128800
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ponesimod 2 to 10 mg film-coated tablets once daily during uptitration phase.

    Investigational medicinal product name
    Teriflunomide Matching Placebo (uptitration)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received teriflunomide matching placebo once daily during uptitration phase.

    Arm title
    		 Teriflunomide 14 mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Teriflunomide 14 mg (maintenance)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received teriflunomide 14 mg over-encapsulated tablets once daily during the maintenance phase.

    Investigational medicinal product name
    Teriflunomide 14 mg (uptitration)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received teriflunomide 14 mg once daily during uptitration phase.

    Investigational medicinal product name
    Ponesimod matching placebo (uptitration)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ponesimod matching placebo once daily during the uptitration phase.

    Number of subjects in period 1
    		Ponesimod 20 mg Teriflunomide 14 mg
    Started
    567
    566
    Completed
    490
    495
    Not completed
    77
    71
         Consent withdrawn by subject
    41
    36
         Death
    -
    2
         Adverse event
    13
    3
         Unspecified
    18
    17
         Lost to follow-up
    2
    3
         Lack of efficacy
    3
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ponesimod 20 mg
    Reporting group description
    		 -

    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 -

    Reporting group values
    		 Ponesimod 20 mg Teriflunomide 14 mg Total
    Number of subjects
    		 567 566 1133
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 567 566 1133
        From 65 to 84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.7 ( 8.74 ) 36.8 ( 8.74 ) -
    Title for Gender
    Units: subjects
        Female
    		 363 372 735
        Male
    		 204 194 398

    End points

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    End points reporting groups
    Reporting group title
    Ponesimod 20 mg
    Reporting group description
    		 -

    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 -

    Primary: Annualized Relapse Rate (ARR)

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    End point title
    		 Annualized Relapse Rate (ARR)
    End point description
    ARR was defined as the number of confirmed relapses according to the treating neurologist or principal investigator per subject-year. A relapse was defined as new, worsening or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours, in the absence of fever or infection. Full Analysis Set (FAS) included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Up to Week 108
    End point values
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Number of subjects analysed
    567
    566
    Units: relapses per year
        least squares mean (confidence interval 99%)
    0.202 (0.165 to 0.246)
    0.290 (0.244 to 0.345)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Ponesimod 20 mg v Teriflunomide 14 mg
    Number of subjects included in analysis
    1133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.695
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.536
         upper limit
    		 0.902

    Secondary: Change from Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ–RMS) Score to Week 108

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    End point title
    		 Change from Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ–RMS) Score to Week 108
    End point description
    FSIQ-RMS is a validated patient-reported outcome instrument. Its symptoms domain assesses multiple sclerosis (MS)-related symptoms of fatigue and has seven items. It has a daily recall period and is administered daily over the course of seven days. Each item of the domain is scored on an 11-point numerical rating scale. The total score for the domain is calculated as the average of the daily symptoms scores over the 7-day period. The domain score is standardized onto a scale of 0 to 100 with higher scores indicating more fatigue. FAS included all randomized subjects. Subjects with baseline and at least one available assessment at a post-baseline visit were included in the analysis. Here 'N' (number of subjects analyzed) signifies number of subjects analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 108
    End point values
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Number of subjects analysed
    499
    458
    Units: score on scale
        least squares mean (confidence interval 95%)
    -0.01 (-1.60 to 1.58)
    3.56 (1.96 to 5.16)
    No statistical analyses for this end point

    Secondary: Cumulative Number of Combined Unique Active Lesions (CUAL) From Baseline to Week 108

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    End point title
    		 Cumulative Number of Combined Unique Active Lesions (CUAL) From Baseline to Week 108
    End point description
    CUALs was calculated as sum of new Gadolinium-enhanced (Gd+) T1 lesions plus new or enlarging T2 lesions (without double-counting of lesions) based on the MRI scans up to Week 108. FAS included all randomized subjects. Here 'N' (number of subjects analyzed) signifies number of subjects analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 108
    End point values
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Number of subjects analysed
    539
    536
    Units: lesions per year
        least squares mean (confidence interval 95%)
    1.405 (1.215 to 1.624)
    3.164 (2.757 to 3.631)
    No statistical analyses for this end point

    Secondary: Event Rate Based on Time to First 12-week Confirmed Disability Accumulation (CDA) From Baseline up to EOS

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    End point title
    		 Event Rate Based on Time to First 12-week Confirmed Disability Accumulation (CDA) From Baseline up to EOS
    End point description
    Time to first 12-week CDA is defined as time from baseline to first onset of a 12-week CDA. A 12-week CDA was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for subjects with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for subjects with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for subjects with a baseline EDSS score greater than or equal to (>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is a disability scale that ranges from 0 (normal) to 10.0 (death) in 0.5-point steps (1-point step from 0 to 1). It is based on standard neurological examination in conjunction with observations concerning ambulation. Percentage (%) of subjects with events (Kaplan-Meier [KM] estimates) were reported. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From Baseline up to EOS (Up to Week 108)
    End point values
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Number of subjects analysed
    567
    566
    Units: percentage of subjects with events
        number (confidence interval 95%)
    10.8 (8.4 to 13.7)
    13.2 (10.6 to 16.3)
    No statistical analyses for this end point

    Secondary: Event Rate Based on Time to First 24-week Confirmed Disability Accumulation (CDA) From Baseline up to EOS

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    End point title
    		 Event Rate Based on Time to First 24-week Confirmed Disability Accumulation (CDA) From Baseline up to EOS
    End point description
    Time to first 24-week CDA is defined as time from baseline to first onset of a 24-week CDA. A 24-week CDA was defined as an increase of at least 1.5 in EDSS for subjects with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for subjects with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for subjects with a baseline EDSS score >= 5.5, which was confirmed after 24 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is a disability scale that ranges from 0 (normal) to 10.0 (death) in 0.5-point steps (1-point step from 0 to 1). It is based on standard neurological examination in conjunction with observations concerning ambulation. The percentage of subjects with events (Kaplan-Meier KM] estimates) was reported. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From Baseline up to EOS (Up to Week 108)
    End point values
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Number of subjects analysed
    567
    566
    Units: percentage of subjects with events
        number (confidence interval 95%)
    8.7 (6.6 to 11.4)
    10.5 (8.2 to 13.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 108
    Adverse event reporting additional description
    The safety analysis set (SAF) included all subjects who received at least one dose of study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ponesimod 20 mg
    Reporting group description
    		 -

    Reporting group title
    Teriflunomide 14 mg
    Reporting group description
    		 -

    Serious adverse events
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 565 (8.67%)
    46 / 566 (8.13%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid Haemangioma
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary Tumour Benign
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of the Cervix
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 565 (0.18%)
    2 / 566 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 565 (0.18%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's Phenomenon
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis Superficial
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion Induced
         subjects affected / exposed
    2 / 565 (0.35%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoid Operation
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament Operation
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Dilation and Curettage
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast Cyst
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial Hyperplasia
         subjects affected / exposed
    1 / 565 (0.18%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 565 (0.18%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 565 (0.00%)
    2 / 566 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Adhesions
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Conversion Disorder
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic Attack
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 565 (0.00%)
    2 / 566 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 565 (0.00%)
    2 / 566 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw Fracture
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament Injury
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Haematoma
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Injury
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Insufficiency
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Clonic Convulsion
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of Consciousness
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    2 / 565 (0.35%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multiple Sclerosis Relapse
         subjects affected / exposed
    1 / 565 (0.18%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial Seizures with Secondary Generalisation
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restless Legs Syndrome
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    3 / 565 (0.53%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel Movement Irregularity
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Haemorrhage
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 565 (0.18%)
    3 / 566 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis Toxic
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial Nephritis
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 565 (0.18%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myofascial Pain Syndrome
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Infection
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 565 (0.53%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph Node Abscess
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Enteroviral
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal Cyst
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 565 (0.18%)
    0 / 566 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 565 (0.00%)
    1 / 566 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ponesimod 20 mg Teriflunomide 14 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    339 / 565 (60.00%)
    343 / 566 (60.60%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    110 / 565 (19.47%)
    51 / 566 (9.01%)
         occurrences all number
    164
    56
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    36 / 565 (6.37%)
    19 / 566 (3.36%)
         occurrences all number
    38
    21
    Vascular disorders
    Hypertension
         subjects affected / exposed
    45 / 565 (7.96%)
    44 / 566 (7.77%)
         occurrences all number
    50
    45
    Nervous system disorders
    Headache
         subjects affected / exposed
    64 / 565 (11.33%)
    72 / 566 (12.72%)
         occurrences all number
    98
    97
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    34 / 565 (6.02%)
    37 / 566 (6.54%)
         occurrences all number
    38
    42
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 565 (3.54%)
    44 / 566 (7.77%)
         occurrences all number
    21
    53
    Nausea
         subjects affected / exposed
    43 / 565 (7.61%)
    47 / 566 (8.30%)
         occurrences all number
    53
    52
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    30 / 565 (5.31%)
    7 / 566 (1.24%)
         occurrences all number
    35
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 565 (3.19%)
    72 / 566 (12.72%)
         occurrences all number
    19
    76
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    33 / 565 (5.84%)
    38 / 566 (6.71%)
         occurrences all number
    40
    40
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    109 / 565 (19.29%)
    95 / 566 (16.78%)
         occurrences all number
    170
    147
    Upper Respiratory Tract Infection
         subjects affected / exposed
    60 / 565 (10.62%)
    59 / 566 (10.42%)
         occurrences all number
    92
    95
    Urinary Tract Infection
         subjects affected / exposed
    31 / 565 (5.49%)
    29 / 566 (5.12%)
         occurrences all number
    39
    48

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2015
    The Amendment-1 included the following main changes: A substudy assessment was added for patient preferences for different outcomes in the treatment of multiple sclerosis (MS) using an electronic MS Patient Preference Questionnaire. In addition, it was clarified that MS relapses were to be reported on the dedicated pages of the electronic Case Report Form (eCRF) and were not to be considered as adverse event (AEs).
    16 Jul 2015
    The Amendment-2 included the following main changes: Introduction of an exclusion criterion in the presence of signs suggestive of progressive multifocal leukoencephalopathy infection which could not be ruled out; Introduction of the electronic self-rated version of the Columbia-Suicide Severity Rating Scale (eC-SSRS) assessment to reliably and consistently monitor subjects for suicidal ideation or behavior during the study; and Monitoring of total white blood cell and total lymphocyte count every 4 weeks up to Week 24.
    05 Feb 2016
    The Amendment-3 included the following main changes: A standardized stepwise procedure for the confirmation and reporting of relapses was introduced. This included incorporating a relapse assessment questionnaire into the study (based on telephone calls and visits); Clarification that the treating neurologist was not to perform the Expanded Disability Status Scale (EDSS) and Functional System (FS) assessment and that no one was to alter EDSS and FS scores recorded by the efficacy assessor; Sensitivity analyses were added for the primary endpoint due to the adjusted collection of data for relapses introduced in this protocol amendment. Some clarifications were added to the existing sensitivity analyses; the definition of baseline assessments was added; the definitions of end of treatment (EOT) and end of study (EOS) were added; and the introduction of an adjudication board for major adverse cardiovascular events (MACE).
    14 Nov 2016
    The Amendment-4 included the following main changes: The procedure for teriflunomide plasma concentration testing after subject’s discontinuation from study treatment was modified and not conducted at Follow-up Visit 1 and Follow-up Visit 2 (15 and 30 days after the last intake of study drug, respectively). This was mainly because an update from the central laboratory (dated 6 October 2016) showed an unexpectedly high number (that is, 33.0 percent [%] of all tests conducted) of reports with alerts indicating teriflunomide plasma concentration above the threshold of 0.02 mg/L. At that time, the total number of affected subjects was 11. The occurrence of these alerts increased the risk of unblinding of the treatment allocation. In addition, in the modified procedure, the timing for the teriflunomide concentration measurement for female subjects of childbearing potential and fertile male subjects was made dependent on compliance with the accelerated elimination procedure to confirm that contraception could be discontinued following treatment discontinuation.
    30 Aug 2017
    The Amendment-5 included the following main changes: Allowed testing of teriflunomide plasma concentration in any subject who had discontinued study drug if deemed necessary for the subject’s safety, at the discretion of the investigator. In this event, the timing of the testing of teriflunomide plasma concentration remained dependent on study drug discontinuation and compliance with the accelerated elimination procedure, as assessed by the investigator. This amendment did not change the procedure for teriflunomide plasma concentration testing to be conducted for female subjects of childbearing potential and fertile male subjects, if needed, to confirm contraception discontinuation.
    05 Dec 2018
    The Amendment-6 included the following main changes: The number of secondary endpoints was reduced from five to four: two endpoints were moved from secondary (time to first relapse and percent change from baseline in brain volume) to exploratory, as these do not add substantial information on clinically important effects of the study drug on MS disease; one endpoint was moved from exploratory (time to 24-week disability) to secondary, to comply with the ʽGuideline on clinical investigation of medicinal products for the treatment of Multiple Sclerosis. The multiple testing strategy to control the Type I error for testing secondary endpoints was modified according to a fallback type method to optimize the ability of the trial to achieve its objectives.

    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.
    Low probability of the AC-058B301 / OPTIMUM study to provide a robust evaluation of the effect of ponesimod on disability accumulation compared to an active comparator.
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