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    Clinical Trial Results:
    Multicenter, Randomized, Double-blind, Parallel-group Extension to Study AC-058B201 to Investigate the Long-term Safety, Tolerability, and Efficacy of 10, 20, and 40 mg/day Ponesimod, an Oral S1P1 Receptor Agonist, in Patients With Relapsing-remitting Multiple Sclerosis

    Summary
    EudraCT number
    		 2009-011470-15
    Trial protocol
    		 FI   SE   ES   GB   CZ   DE   BG   PL   HU   NL   AT   IT  
    Global end of trial date
    06 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2024
    First version publication date
    19 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-058B202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01093326
    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
    06 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial were to investigate the long-term safety, tolerability and efficacy of ponesimod in subjects with relapsing-remitting multiple sclerosis.
    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 and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 May 2010
    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
    Austria: 8
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Czechia: 43
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Finland: 16
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 40
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    Ukraine: 16
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    353
    EEA total number of subjects
    187
    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)
    353
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Total 353 subjects entered this extension study after completing the core study (NCT01006265) and were randomised as: 115 in ponesimod 10 mg, 121 in ponesimod 20 mg, and 117 in ponesimod 40 mg. Total 227 subjects completed the study. As planned, combined analysis (core plus extension study) was done for efficacy and safety (435 subjects).

    Pre-assignment
    Screening details
    		 Data reported in each arm are based on first dose received during treatment period (TP) 1.

    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, Monitor, Assessor, Carer, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ponesimod 10 Milligrams (mg)
    Arm description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 10 mg or placebo, entered this extension study and received ponesimod 10 mg capsules orally once daily during treatment period (TP) 1. Subjects continued to receive ponesimod 10 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ponesimod 10 mg
    Investigational medicinal product code
    JNJ-67896153; ACT-128800
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ponesimod 10 mg orally once daily.

    Arm title
    		 Ponesimod 20 Milligrams (mg)
    Arm description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 20 mg or placebo, entered this extension study and received ponesimod 20 mg capsules orally once daily during TP1. Subjects continued to receive ponesimod 20 mg tablet orally, once daily during TP2 and TP3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ponesimod 20 mg
    Investigational medicinal product code
    JNJ-67896153; ACT-128800
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ponesimod 20 mg orally once daily.

    Arm title
    		 Ponesimod 40 Milligrams (mg)
    Arm description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 40 mg or placebo, entered this extension study and received ponesimod 40 mg capsules orally once daily during TP1. Subjects were then re-randomised to receive ponesimod 10 or 20 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ponesimod 40 mg
    Investigational medicinal product code
    JNJ-67896153; ACT-128800
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ponesimod 40 mg orally once daily.

    Number of subjects in period 1
    		Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Started
    115
    121
    117
    Completed
    71
    80
    76
    Not completed
    44
    41
    41
         Adverse event, serious fatal
    -
    1
    -
         Physician decision
    3
    1
    3
         Consent withdrawn by subject
    30
    27
    26
         Adverse event, non-fatal
    2
    1
    4
         Unspecified
    -
    -
    1
         Lost to follow-up
    2
    5
    4
         Lack of efficacy
    7
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ponesimod 10 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 10 mg or placebo, entered this extension study and received ponesimod 10 mg capsules orally once daily during treatment period (TP) 1. Subjects continued to receive ponesimod 10 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Reporting group title
    Ponesimod 20 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 20 mg or placebo, entered this extension study and received ponesimod 20 mg capsules orally once daily during TP1. Subjects continued to receive ponesimod 20 mg tablet orally, once daily during TP2 and TP3.

    Reporting group title
    Ponesimod 40 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 40 mg or placebo, entered this extension study and received ponesimod 40 mg capsules orally once daily during TP1. Subjects were then re-randomised to receive ponesimod 10 or 20 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Reporting group values
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg) Total
    Number of subjects
    		 115 121 117 353
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 115 121 117 353
        From 65 to 84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.6 ( 8.67 ) 36.1 ( 8.58 ) 35.9 ( 8.61 ) -
    Title for Gender
    Units: subjects
        Female
    		 77 80 76 233
        Male
    		 38 41 41 120

    End points

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    End points reporting groups
    Reporting group title
    Ponesimod 10 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 10 mg or placebo, entered this extension study and received ponesimod 10 mg capsules orally once daily during treatment period (TP) 1. Subjects continued to receive ponesimod 10 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Reporting group title
    Ponesimod 20 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 20 mg or placebo, entered this extension study and received ponesimod 20 mg capsules orally once daily during TP1. Subjects continued to receive ponesimod 20 mg tablet orally, once daily during TP2 and TP3.

    Reporting group title
    Ponesimod 40 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 40 mg or placebo, entered this extension study and received ponesimod 40 mg capsules orally once daily during TP1. Subjects were then re-randomised to receive ponesimod 10 or 20 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Subject analysis set title
    Ponesimod 10 Milligrams (mg)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 10 mg or placebo, entered this extension study and received ponesimod 10 mg capsules orally once daily during treatment period (TP) 1. Subjects continued to receive ponesimod 10 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Subject analysis set title
    Ponesimod 20 Milligrams (mg)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 20 mg or placebo, entered this extension study and received ponesimod 20 mg capsules orally once daily during TP1. Subjects continued to receive ponesimod 20 mg tablet orally, once daily during TP2 and TP3.

    Subject analysis set title
    Ponesimod 40 Milligrams (mg)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 40 mg or placebo, entered this extension study and received ponesimod 40 mg capsules orally once daily during TP1. Subjects were then re-randomised to receive ponesimod 10 or 20 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Primary: Annualized Relapse Rate (ARR) of Confirmed Relapses

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    End point title
    		 Annualized Relapse Rate (ARR) of Confirmed Relapses [1]
    End point description
    ARR is defined as the number of confirmed relapses per year. A relapse is defined as the occurrence of an acute episode of one or more new symptoms, or worsening of existing symptoms of multiple sclerosis (MS), not associated with fever or infection, and lasting for at least 24 hours after a stable period of at least 30 days. A confirmed relapse is a relapse accompanied by an increase from the previous clinically stable assessment (that is, performed at least 30 days after the onset of any previous relapse) of at least 0.5 point in the Expanded Disability Status Scale (EDSS) score, or one point in the score for at least one of the Functional System (FS) scores, excluding the bowel and bladder, and mental FS. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10 (death due to MS). Ponesimod analysis set (PAS) included all subjects who received at least one dose of ponesimod at any time during the core and/or the extension study (435 subjects).
    End point type
    Primary
    End point timeframe
    From ponesimod start date up to the end of Analysis Period (AP) 3. The actual time varied for each subject and could be up to 13.3 years
    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: No inferential statistics were planned for this endpoint. Descriptive statistics were only reported.
    End point values
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Number of subjects analysed
    139
    145
    151
    Units: Confirmed relapses per year
        arithmetic mean (confidence interval 95%)
    0.205 (0.150 to 0.282)
    0.142 (0.102 to 0.198)
    0.150 (0.105 to 0.215)
    No statistical analyses for this end point

    Primary: Time to First Confirmed Relapse

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    End point title
    		 Time to First Confirmed Relapse [2]
    End point description
    Time to first confirmed relapse was reported. A relapse is defined as the occurrence of an acute episode of one or more new symptoms or worsening of existing symptoms of multiple sclerosis (MS), not associated with fever or infection, and lasting for at least 24 hours after a stable period of at least 30 days. A confirmed relapse is accompanied by an increase from the previous clinically stable assessment (that is, performed at least 30 days after the onset of any previous relapse) of at least 0.5 point in the EDDS score, or one point in the score for at least one of the FS scores, excluding the bowel and bladder, and mental FS. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10 (death due to MS). PAS included all subjects who received at least one dose of ponesimod at any time during the core and/or the extension study (435 subjects). Here, '99999' refers data was not estimable due to less number of subjects with event.
    End point type
    Primary
    End point timeframe
    From ponesimod start date up to the end of Analysis Period (AP) 3. The actual time varied for each subject and could be up to 13.3 years
    Notes
    [2] - 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: No inferential statistics were planned for this endpoint. Descriptive statistics were only reported.
    End point values
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Number of subjects analysed
    139
    145
    151
    Units: Weeks
        median (confidence interval 95%)
    272.3 (164.6 to 99999)
    656.7 (278.0 to 99999)
    431.7 (296.3 to 99999)
    No statistical analyses for this end point

    Primary: Time to 24 Weeks Confirmed Disability Progression

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    End point title
    		 Time to 24 Weeks Confirmed Disability Progression [3]
    End point description
    Time to 24 weeks confirmed disability progression (accumulation) was reported. Disability progression defined as an increase of at least 1 point in the EDSS score if baseline EDSS was between 1 and 5.0, an increase of at least 1.5 points if baseline EDSS was 0, or an increase of at least 0.5 points if the baseline EDSS was equal or greater than 5.5. A 24-week confirmed disability progression is defined as a 24-week sustained increase from baseline in the EDSS scores, that is, every EDSS score (scheduled or unscheduled, with or without relapse) within a 24-week duration after the first progression should meet the progression criteria. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10 (death due to MS). PAS included all subjects who received at least one dose of ponesimod at any time during the core and/or the extension study (435 subjects). Here, '99999' refers data was not estimable due to less number of subjects with event.
    End point type
    Primary
    End point timeframe
    From ponesimod baseline up to the end of Analysis Period (AP) 3. The actual time varied for each subject and could be up to 13.3 years
    Notes
    [3] - 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: No inferential statistics were planned for this endpoint. Descriptive statistics were only reported.
    End point values
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Number of subjects analysed
    139
    145
    151
    Units: Weeks
        median (confidence interval 95%)
    99999 (470.3 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With At least One Treatment-emergent Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With At least One Treatment-emergent Serious Adverse Events (SAEs)
    End point description
    Number of subjects with at least one treatment-emergent SAEs were reported. An adverse event (AE) is any untoward medical occurrence in a subject participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; suspected transmission of any infectious agent via a medicinal product or medically important. Treatment-emergent SAEs are SAEs that occurred at or after initial administration of ponesimod up to 15 days (inclusive) after last administration of ponesimod. Ponesimod analysis set included all subjects who received at least one dose of ponesimod at any time during the core and/or the extension study (435 subjects).
    End point type
    Other pre-specified
    End point timeframe
    From ponesimod start date up to the end of study treatment + 15 Days. The actual time of observation varied for each subject and could be up to 12.97 years + 15 days
    End point values
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Number of subjects analysed
    139
    145
    151
    Units: Subjects
    32
    35
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For Serious and Non-serious AEs: From ponesimod start date up to end of treatment + 15 days (up to 12.97 years + 15 days); For Death: From ponesimod start date to end of AP3 (up to 13.3 years)
    Adverse event reporting additional description
    Ponesimod analysis set included all subjects who received at least one dose of ponesimod at any time during the core and/or the extension study (435 subjects).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Ponesimod 10 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 10 mg or placebo, entered this extension study and received ponesimod 10 mg capsules orally once daily during treatment period (TP) 1. Subjects continued to receive ponesimod 10 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Reporting group title
    Ponesimod 20 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 20 mg or placebo, entered this extension study and received ponesimod 20 mg capsules orally once daily during TP1. Subjects continued to receive ponesimod 20 mg tablet orally, once daily during TP2 and TP3.

    Reporting group title
    Ponesimod 40 Milligrams (mg)
    Reporting group description
    		 Subjects with relapsing-remitting multiple sclerosis having completed their regular Week 24 treatment visit of the core study (2008-006786-92) while receiving ponesimod 40 mg or placebo, entered this extension study and received ponesimod 40 mg capsules orally once daily during TP1. Subjects were then re-randomised to receive ponesimod 10 or 20 mg tablet orally, once daily during TP2. All subjects received ponesimod 20 mg tablet orally, once daily during TP3.

    Serious adverse events
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 139 (23.02%)
    35 / 145 (24.14%)
    25 / 151 (16.56%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of the Cervix
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 145 (1.38%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-Cell Lymphoma
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 145 (0.69%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Hydatidiform Mole
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix Carcinoma Stage 0
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal Papilloma of Breast
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    3 / 139 (2.16%)
    2 / 145 (1.38%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phaeochromocytoma
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary Thyroid Cancer
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose Vein
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 145 (0.69%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Oophorectomy
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicectomy
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abortion Induced
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial Hyperplasia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermenstrual Bleeding
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 145 (1.38%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Polyp
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Prolapse
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute Stress Disorder
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Magnetic Resonance Imaging Abnormal
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT Prolonged
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal Injury
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Contusion
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chemical Burn of Skin
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Injury
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture Displacement
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 145 (1.38%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular Block Second Degree
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Prolapse
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lumbar Radiculopathy
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical Radiculopathy
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Altered State of Consciousness
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postictal State
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tension Headache
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Microcytic Anaemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular Oedema
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 145 (1.38%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract Nuclear
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular Hole
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhegmatogenous Retinal Detachment
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Maculopathy
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Incontinence
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer Perforation
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 145 (1.38%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatosplenomegaly
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot Deformity
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal Abscess
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complicated Appendicitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Hepatitis C
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 145 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 145 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 145 (0.69%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ponesimod 10 Milligrams (mg) Ponesimod 20 Milligrams (mg) Ponesimod 40 Milligrams (mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    121 / 139 (87.05%)
    125 / 145 (86.21%)
    140 / 151 (92.72%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic Naevus
         subjects affected / exposed
    7 / 139 (5.04%)
    8 / 145 (5.52%)
    8 / 151 (5.30%)
         occurrences all number
    7
    10
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 139 (15.83%)
    19 / 145 (13.10%)
    18 / 151 (11.92%)
         occurrences all number
    24
    22
    23
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 139 (9.35%)
    18 / 145 (12.41%)
    14 / 151 (9.27%)
         occurrences all number
    15
    21
    21
    Oedema Peripheral
         subjects affected / exposed
    3 / 139 (2.16%)
    8 / 145 (5.52%)
    16 / 151 (10.60%)
         occurrences all number
    3
    8
    17
    Pyrexia
         subjects affected / exposed
    5 / 139 (3.60%)
    8 / 145 (5.52%)
    7 / 151 (4.64%)
         occurrences all number
    6
    8
    11
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    11 / 139 (7.91%)
    11 / 145 (7.59%)
    11 / 151 (7.28%)
         occurrences all number
    11
    13
    13
    Obstructive Airways Disorder
         subjects affected / exposed
    7 / 139 (5.04%)
    11 / 145 (7.59%)
    8 / 151 (5.30%)
         occurrences all number
    7
    11
    9
    Dyspnoea
         subjects affected / exposed
    10 / 139 (7.19%)
    10 / 145 (6.90%)
    21 / 151 (13.91%)
         occurrences all number
    10
    14
    25
    Cough
         subjects affected / exposed
    11 / 139 (7.91%)
    13 / 145 (8.97%)
    28 / 151 (18.54%)
         occurrences all number
    18
    16
    37
    Asthma
         subjects affected / exposed
    6 / 139 (4.32%)
    5 / 145 (3.45%)
    8 / 151 (5.30%)
         occurrences all number
    7
    5
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 139 (6.47%)
    11 / 145 (7.59%)
    11 / 151 (7.28%)
         occurrences all number
    10
    15
    14
    Depression
         subjects affected / exposed
    8 / 139 (5.76%)
    11 / 145 (7.59%)
    9 / 151 (5.96%)
         occurrences all number
    8
    12
    13
    Anxiety
         subjects affected / exposed
    8 / 139 (5.76%)
    9 / 145 (6.21%)
    8 / 151 (5.30%)
         occurrences all number
    12
    9
    10
    Investigations
    Pulmonary Function Test Decreased
         subjects affected / exposed
    5 / 139 (3.60%)
    2 / 145 (1.38%)
    8 / 151 (5.30%)
         occurrences all number
    8
    3
    9
    Forced Vital Capacity Decreased
         subjects affected / exposed
    9 / 139 (6.47%)
    3 / 145 (2.07%)
    7 / 151 (4.64%)
         occurrences all number
    18
    4
    11
    Forced Expiratory Volume Decreased
         subjects affected / exposed
    14 / 139 (10.07%)
    12 / 145 (8.28%)
    17 / 151 (11.26%)
         occurrences all number
    22
    23
    31
    Blood Cholesterol Increased
         subjects affected / exposed
    7 / 139 (5.04%)
    4 / 145 (2.76%)
    6 / 151 (3.97%)
         occurrences all number
    14
    4
    9
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    6 / 139 (4.32%)
    10 / 145 (6.90%)
    8 / 151 (5.30%)
         occurrences all number
    7
    13
    17
    Alanine Aminotransferase Increased
         subjects affected / exposed
    16 / 139 (11.51%)
    19 / 145 (13.10%)
    19 / 151 (12.58%)
         occurrences all number
    25
    38
    43
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    9 / 139 (6.47%)
    8 / 145 (5.52%)
    8 / 151 (5.30%)
         occurrences all number
    11
    12
    9
    Ligament Sprain
         subjects affected / exposed
    7 / 139 (5.04%)
    10 / 145 (6.90%)
    3 / 151 (1.99%)
         occurrences all number
    8
    12
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 139 (12.95%)
    14 / 145 (9.66%)
    18 / 151 (11.92%)
         occurrences all number
    18
    16
    24
    Headache
         subjects affected / exposed
    38 / 139 (27.34%)
    31 / 145 (21.38%)
    41 / 151 (27.15%)
         occurrences all number
    62
    79
    91
    Paraesthesia
         subjects affected / exposed
    7 / 139 (5.04%)
    7 / 145 (4.83%)
    6 / 151 (3.97%)
         occurrences all number
    12
    8
    8
    Multiple Sclerosis
         subjects affected / exposed
    7 / 139 (5.04%)
    5 / 145 (3.45%)
    1 / 151 (0.66%)
         occurrences all number
    9
    5
    1
    Migraine
         subjects affected / exposed
    9 / 139 (6.47%)
    9 / 145 (6.21%)
    12 / 151 (7.95%)
         occurrences all number
    15
    13
    18
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    5 / 139 (3.60%)
    6 / 145 (4.14%)
    8 / 151 (5.30%)
         occurrences all number
    5
    9
    13
    Anaemia
         subjects affected / exposed
    7 / 139 (5.04%)
    10 / 145 (6.90%)
    7 / 151 (4.64%)
         occurrences all number
    9
    15
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 139 (1.44%)
    7 / 145 (4.83%)
    8 / 151 (5.30%)
         occurrences all number
    2
    18
    9
    Eye disorders
    Eye Pain
         subjects affected / exposed
    7 / 139 (5.04%)
    3 / 145 (2.07%)
    3 / 151 (1.99%)
         occurrences all number
    20
    4
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    7 / 139 (5.04%)
    4 / 145 (2.76%)
    4 / 151 (2.65%)
         occurrences all number
    7
    4
    5
    Nausea
         subjects affected / exposed
    4 / 139 (2.88%)
    7 / 145 (4.83%)
    10 / 151 (6.62%)
         occurrences all number
    4
    8
    10
    Diarrhoea
         subjects affected / exposed
    12 / 139 (8.63%)
    11 / 145 (7.59%)
    9 / 151 (5.96%)
         occurrences all number
    22
    13
    10
    Constipation
         subjects affected / exposed
    4 / 139 (2.88%)
    8 / 145 (5.52%)
    3 / 151 (1.99%)
         occurrences all number
    4
    8
    4
    Abdominal Pain Upper
         subjects affected / exposed
    5 / 139 (3.60%)
    4 / 145 (2.76%)
    9 / 151 (5.96%)
         occurrences all number
    8
    4
    9
    Toothache
         subjects affected / exposed
    6 / 139 (4.32%)
    8 / 145 (5.52%)
    9 / 151 (5.96%)
         occurrences all number
    6
    9
    10
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 139 (5.04%)
    9 / 145 (6.21%)
    5 / 151 (3.31%)
         occurrences all number
    7
    9
    6
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    21 / 139 (15.11%)
    23 / 145 (15.86%)
    22 / 151 (14.57%)
         occurrences all number
    26
    29
    31
    Arthralgia
         subjects affected / exposed
    21 / 139 (15.11%)
    16 / 145 (11.03%)
    16 / 151 (10.60%)
         occurrences all number
    28
    23
    22
    Muscle Spasms
         subjects affected / exposed
    7 / 139 (5.04%)
    4 / 145 (2.76%)
    8 / 151 (5.30%)
         occurrences all number
    11
    4
    11
    Pain in Extremity
         subjects affected / exposed
    7 / 139 (5.04%)
    14 / 145 (9.66%)
    9 / 151 (5.96%)
         occurrences all number
    7
    16
    9
    Infections and infestations
    Herpes Zoster
         subjects affected / exposed
    4 / 139 (2.88%)
    9 / 145 (6.21%)
    6 / 151 (3.97%)
         occurrences all number
    4
    9
    6
    Bronchitis
         subjects affected / exposed
    22 / 139 (15.83%)
    22 / 145 (15.17%)
    21 / 151 (13.91%)
         occurrences all number
    38
    30
    30
    Conjunctivitis
         subjects affected / exposed
    9 / 139 (6.47%)
    3 / 145 (2.07%)
    2 / 151 (1.32%)
         occurrences all number
    11
    5
    2
    Covid-19
         subjects affected / exposed
    12 / 139 (8.63%)
    19 / 145 (13.10%)
    19 / 151 (12.58%)
         occurrences all number
    13
    23
    23
    Cystitis
         subjects affected / exposed
    7 / 139 (5.04%)
    8 / 145 (5.52%)
    9 / 151 (5.96%)
         occurrences all number
    14
    8
    15
    Gastroenteritis
         subjects affected / exposed
    11 / 139 (7.91%)
    10 / 145 (6.90%)
    7 / 151 (4.64%)
         occurrences all number
    18
    15
    12
    Gastroenteritis Viral
         subjects affected / exposed
    5 / 139 (3.60%)
    8 / 145 (5.52%)
    5 / 151 (3.31%)
         occurrences all number
    5
    14
    8
    Viral Infection
         subjects affected / exposed
    7 / 139 (5.04%)
    9 / 145 (6.21%)
    8 / 151 (5.30%)
         occurrences all number
    8
    19
    15
    Urinary Tract Infection
         subjects affected / exposed
    21 / 139 (15.11%)
    21 / 145 (14.48%)
    22 / 151 (14.57%)
         occurrences all number
    79
    68
    45
    Upper Respiratory Tract Infection
         subjects affected / exposed
    27 / 139 (19.42%)
    28 / 145 (19.31%)
    39 / 151 (25.83%)
         occurrences all number
    84
    87
    109
    Tonsillitis
         subjects affected / exposed
    7 / 139 (5.04%)
    6 / 145 (4.14%)
    2 / 151 (1.32%)
         occurrences all number
    12
    7
    2
    Sinusitis
         subjects affected / exposed
    12 / 139 (8.63%)
    12 / 145 (8.28%)
    15 / 151 (9.93%)
         occurrences all number
    17
    26
    22
    Rhinitis
         subjects affected / exposed
    14 / 139 (10.07%)
    12 / 145 (8.28%)
    2 / 151 (1.32%)
         occurrences all number
    21
    12
    2
    Respiratory Tract Infection
         subjects affected / exposed
    12 / 139 (8.63%)
    12 / 145 (8.28%)
    9 / 151 (5.96%)
         occurrences all number
    22
    13
    11
    Pharyngitis
         subjects affected / exposed
    12 / 139 (8.63%)
    4 / 145 (2.76%)
    7 / 151 (4.64%)
         occurrences all number
    21
    4
    11
    Nasopharyngitis
         subjects affected / exposed
    46 / 139 (33.09%)
    46 / 145 (31.72%)
    45 / 151 (29.80%)
         occurrences all number
    142
    106
    136
    Influenza
         subjects affected / exposed
    20 / 139 (14.39%)
    18 / 145 (12.41%)
    20 / 151 (13.25%)
         occurrences all number
    48
    51
    43
    Oral Herpes
         subjects affected / exposed
    9 / 139 (6.47%)
    6 / 145 (4.14%)
    9 / 151 (5.96%)
         occurrences all number
    42
    12
    16
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    5 / 139 (3.60%)
    8 / 145 (5.52%)
    7 / 151 (4.64%)
         occurrences all number
    5
    8
    7
    Hypercholesterolaemia
         subjects affected / exposed
    14 / 139 (10.07%)
    16 / 145 (11.03%)
    10 / 151 (6.62%)
         occurrences all number
    16
    16
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2010
    The B202 extension study protocol was adjusted to reflect changes introduced in the B201 core study protocol, as follows: a) Update of ponesimod effects in humans with data from study AC-058A200; b) Adjust the list of prohibited concomitant medications in the extension protocol B202 to reflect recent changes in the core protocol B201.
    16 Feb 2012
    The amendment was to : a) The ponesimod 40 mg treatment arm was stopped and subjects from this treatment arm were re-randomized to either ponesimod 10 mg or 20 mg; b) Introduction of TP2; c) Extension of ponesimod treatment by an additional 144 weeks (approximately 3 years) with 10 and 20 mg ponesimod in tablet formulation (that is, new formulation); d) Dose-response relationship of ponesimod doses with lymphocyte counts, MRI-related endpoints and ARRs were introduced as additional objectives.
    09 Sep 2013
    Upon issuance of the B201 CSR, information regarding study blinding was updated to indicate that the sponsor is now unblinded. Investigators, subjects and non-sponsor ancillary personnel are still blinded.
    09 Oct 2014
    Ponesimod treatment duration was extended by an additional 288 weeks (5.5 years) or until commercial availability of ponesimod for treatment of MS in the subject’s country, whichever comes first.
    06 Nov 2014
    Requirements for contraceptive methods were modified (that is, a sperm immobilizing agent was added as an option in case no spermicide is commercially available).
    29 Oct 2015
    The reason for amendments was: a) Amendment of the definition of a “confirmed relapse”; b) Modification of the requirements for contraceptive methods (that is, a contraceptive method from the Group 2 can be used without combining it with a spermicide or a sperm immobilizing agent); c) Alignment with the information contained in the Investigator’s Brochure on the risk of hypertension.
    29 Mar 2017
    The reason for amendment was: a) To introduce TP3, during which all subjects will receive ponesimod 20 mg. This was based on a recommendation from the IDMC; results from an analysis comparing safety and efficacy outcomes of the 2 doses of ponesimod currently used in the study, 10 mg and 20 mg, suggested that the 20 mg dose had a better efficacy than the 10 mg dose, with a similar safety profile; b) To allow women of childbearing potential who wish to become pregnant to stay in the study, provided that the study drug had been interrupted prior to pregnancy and reinitiated only after delivery (and after breastfeeding had been stopped).
    14 May 2020
    The reason for amendment was: a) To extend the duration of ponesimod treatment by up to an additional 108 weeks (2.1 years) in order to ensure treatment continuity until commercial availability in the subject’s country. As a result, the combined duration of TP2 and TP3 was extended up to a maximum of 540 weeks; b) To introduce the 2-week gradual up-titration regimen, to be used in case of re-initiation of study drug during TP3; c) To amend the guidance for re-initiation of study treatment in the event of study treatment interruption in order to allow subjects without the identified cardiovascular risk factors to reinitiate study drug at home; d) To provide guidance regarding conduct of the study during the COVID-19 (coronavirus) pandemic; e) To introduce guidance for subject monitoring and discontinuation in case of liver enzyme abnormalities; f) To align the cardiovascular criteria for discontinuation with that used in Phase 3 clinical studies with ponesimod.
    19 Oct 2020
    The reason for amendment was: a) To inform study sites that the IDMC will be disbanded after the clinical database closure of the last ponesimod double-blind study, in line with the disbandment date agreed per the IDMC Charter; b) To provide further guidance on study conduct if/when ponesimod becomes commercially available during the study and subjects are switched from study drug to commercially available ponesimod; c) To align the safety reporting procedures with Janssen Safety processes and standards following the integration of Actelion Safety into Janssen Safety; d) To clarify procedures related to the reporting of MS relapses and align with the wording in the protocol for the ongoing Phase 3 study (AC-058B303/OPTIMUM-LT).
    04 May 2021
    The reason for amendment was: a) To align instructions related to vaccination to those in the Investigator’s Brochure; b) To introduce the transition of paper Case Report Form (CRF) to electronic Case Report Form (eCRF); c) To further clarify guidance regarding conduct of the study during the COVID-19 (coronavirus) pandemic and the deployment of COVID-19 vaccines; d) To update sponsor contact information.
    15 Mar 2022
    The reason for amendments was: a) To allow any EDSS/FS tool which is used at the site as a standard instrument; b) To introduce immunogenicity analysis into the statistical section; c) To remove the bronchodilator test at the scheduled PFT due to the prolonged length of the study; d) To narrow the scope of vaccine-specific antibody titers from pre- to post-vaccination to subjects having received non-live vaccination against influenza or COVID-19 while on study treatment; e) To update the requirement for OCT to be performed only in the case of visual symptoms suggestive of macular edema or active uveitis, as consistent with the observed dynamic of this event on S1P treatment; f) To acknowledge the decommission of the OSB; g) To confirm the disbandment of the IDMC.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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