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    Clinical Trial Results:
    A Phase 2/3, Multi-center, Randomized, Double-blind, Placebo-controlled (Part A) and Double-Blind, Double-dummy, Active-controlled (Part B), Parallel Group Study to Evaluate the Efficacy and Safety of RPC1063 Administered Orally to Relapsing Multiple Sclerosis Patients

    Summary
    EudraCT number
    2012-002714-40
    Trial protocol
    IT   BE   ES   HU   BG   GR   GB   SK   HR  
    Global end of trial date
    13 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    24 May 2018
    First version publication date
    24 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RPC01-201-PartA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01628393
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene International Sarle II
    Sponsor organisation address
    Rue des Moulins 4, Couvet, Switzerland,
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 8882601599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    James Sheffield, Celgene Corporation, 01 619-371-1506, JSheffield@Celgene.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
    12 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To demonstrate the superior clinical efficacy of RPC1063 compared to placebo by showing a reduction in the cumulative number of total gadolinium enhancing (GdE) lesions from Week 12 to Week 24 in patients with relapsing multiple sclerosis (RMS). Part B: To assess whether the clinical efficacy of RPC1063 is superior to IFN-1a (Avonex®) in reducing the rate of clinical relapses at the end of Month 24 in patients with RMS.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection. This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Georgia: 41
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Poland: 507
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Russian Federation: 140
    Country: Number of subjects enrolled
    Serbia: 140
    Country: Number of subjects enrolled
    Spain: 61
    Country: Number of subjects enrolled
    Ukraine: 261
    Country: Number of subjects enrolled
    United States: 59
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Belarus: 116
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 8
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Croatia: 45
    Country: Number of subjects enrolled
    Moldova, Republic of: 9
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    South Africa: 18
    Country: Number of subjects enrolled
    United Kingdom: 16
    Worldwide total number of subjects
    1578
    EEA total number of subjects
    784
    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)
    1578
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Part A of the study was conducted at 55 study centers in 13 countries including the United States, Europe and Russia and consisted of a 24-week placebo-controlled period and an optional 96-week extension period. Part B was performed at 150 sites in North America, Europe, and South Africa with a overall treatment period of 24 months.

    Pre-assignment
    Screening details
    Part A subjects were randomly assigned to one of two daily doses of ozanimod 0.5 mg or 1 mg or placebo for 24 weeks. Those who completed 24 weeks could enter an extension phase and continue ozanimod 0.5 mg or 1 mg daily; Part B subjects were randomly assigned to one of two daily doses of ozanimod 0.5 mg or 1 mg or weekly Interferon injection.

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    A “dual assessor” approach was used to evaluate efficacy and safety to prevent potential unblinding as result of observed efficacy, adverse events, (AEs) or laboratory changes. A patients treatment group assignment blind was not to be broken until the end of the study unless medical treatment of that patient depened upon knowing whether the patient was receiving active drug.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo (Part A Core)
    Arm description
    Participants received placebo capsules (identical in appearance to ozanimod) by mouth (PO) daily during the 24-week placebo-controlled phase. Participants were given the option to enter into a blinded extension phase and were re-randomized to receive ozanimod 0.5 mg or 1mg capsules PO daily for an additional 96 weeks of treatment.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules (identical in appearance to ozanimod) PO daily for 24 weeks

    Arm title
    Ozanimod 0.5 mg (Part A Core)
    Arm description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 0.5 mg capsules PO daily for an additional 96 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    Other name
    RPC1063
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 0.5 mg capsules PO daily for 24 weeks

    Arm title
    Ozanimod 1 mg (Part A Core)
    Arm description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. These participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    Other name
    RPC1063
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 1 mg capsules PO daily for 24 weeks.

    Arm title
    Interferon Beta-1a (IFN β-1a) (Part B)
    Arm description
    Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    Interferon Beta - 1a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IFN β-1a 30 µg intramuscular (IM) injection weekly for two years.

    Arm title
    Ozanimod 0.5 mg (Part B)
    Arm description
    Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    Other name
    RPC1063
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 0.5 mg capsules PO daily for two years

    Arm title
    Ozanimod 1 mg (Part B)
    Arm description
    Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months
    Arm type
    Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    Other name
    RPC1063
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 1 mg capsules PO daily for two years.

    Number of subjects in period 1
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core) Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Started
    88
    87
    83
    443
    443
    434
    Received Treatment
    88
    87
    83
    441
    439
    433
    Completed
    85
    85
    82
    376
    374
    388
    Not completed
    3
    2
    1
    67
    69
    46
         Protocol deviation
    -
    1
    -
    3
    1
    1
         Physician decision
    -
    -
    -
    7
    6
    5
         Miscellaneous
    -
    -
    -
    2
    4
    6
         Randomized; no study drug received
    -
    -
    -
    2
    4
    1
         Lack of efficacy
    -
    -
    -
    4
    5
    1
         Adverse event, serious fatal
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    18
    13
    13
         Consent withdrawn by subject
    2
    1
    1
    30
    31
    19
         Lost to follow-up
    1
    -
    -
    1
    4
    -
    Period 2
    Period 2 title
    Part A: Blinded Active Extension Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    During the blinded extension phase of Part A, the sponsor and Clinical Research Organization (CRO) were blinded until the Week 24 primary endpoint was reached by all patients and the data through Week 24 was finalized, after which the sponsor and CRO were unblinded to the treatment assignment. Investigators and patients remained blinded throughout the extension phase.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo-Ozanimod 0.5 mg (Part A Extension)
    Arm description
    Participants initially randomized to placebo capsules PO daily during the 24-week placebo controlled treatment phase were re-randomized to receive ozanimod 0.5 mg capsules during the optional blinded extension period for an additional 96 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Ozanimod
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 0.5 mg capsules PO daily during the 96-week extension phase.

    Arm title
    Ozanimod 0.5 mg - 0.5 mg (Part A Extension)
    Arm description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 0.5 mg capsules PO daily for an additional 96 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Ozanimod
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 0.5 mg capsules PO daily during the 96-week extension phase.

    Arm title
    Placebo-Ozanimod 1 mg (Part A Extension)
    Arm description
    Participants initially randomized to placebo capsules PO daily during the 24-week placebo controlled treatment phase were re-randomized to receive ozanimod 1 mg capsules during the optional blinded extension period for an additional 96 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Ozanimod
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 1 mg capsules PO daily during the 96-week extension phase.

    Arm title
    Ozanimod 1 mg - 1mg (Part A Extension)
    Arm description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Ozanimod
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 1 mg capsules PO daily during the 96-week extension phase.

    Number of subjects in period 2 [1]
    Placebo-Ozanimod 0.5 mg (Part A Extension) Ozanimod 0.5 mg - 0.5 mg (Part A Extension) Placebo-Ozanimod 1 mg (Part A Extension) Ozanimod 1 mg - 1mg (Part A Extension)
    Started
    41
    85
    42
    81
    Completed
    37
    75
    36
    75
    Not completed
    4
    10
    6
    6
         Protocol deviation
    1
    -
    -
    -
         Physician decision
    1
    3
    -
    2
         Lack of efficacy
    -
    -
    2
    2
         Adverse event, non-fatal
    2
    1
    2
    -
         Consent withdrawn by subject
    -
    6
    2
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects were given the option to participate in the blinded active extension phase and some subjects chose not to participate.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Part A Core)
    Reporting group description
    Participants received placebo capsules (identical in appearance to ozanimod) by mouth (PO) daily during the 24-week placebo-controlled phase. Participants were given the option to enter into a blinded extension phase and were re-randomized to receive ozanimod 0.5 mg or 1mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Ozanimod 0.5 mg (Part A Core)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 0.5 mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Ozanimod 1 mg (Part A Core)
    Reporting group description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. These participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Interferon Beta-1a (IFN β-1a) (Part B)
    Reporting group description
    Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

    Reporting group title
    Ozanimod 0.5 mg (Part B)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

    Reporting group title
    Ozanimod 1 mg (Part B)
    Reporting group description
    Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months

    Reporting group values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core) Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B) Total
    Number of subjects
    88 87 83 443 443 434 1578
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0
        Adults (18-64 years)
    88 87 83 443 443 434 1578
        From 65-84 years
    0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.0 ± 8.67 38.1 ± 9.17 38.4 ± 40.0 35.1 ± 9.1 35.5 ± 8.82 36.0 ± 8.88 -
    Sex: Female, Male
    Units: Subjects
        Female
    62 60 59 305 289 292 1067
        Male
    26 27 24 138 154 142 511
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    87 84 83 432 431 428 1545
        Black|
    1 2 0 7 6 5 21
        Asian|
    0 1 0 1 0 0 2
        Other
    0 0 0 3 6 1 10
    Region, Category
    Units: Subjects
        North America
    4 4 4 16 16 16 60
        Western Europe
    6 4 3 40 40 36 129
        Eastern Europe
    78 79 76 379 378 374 1364
        South Africa
    0 0 0 6 5 7 18
        Missing
    0 0 0 2 4 1 7
    Age at Multiple Sclerosis Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    33.9 ± 8.30 34.8 ± 10.01 34.4 ± 9.51 31.6 ± 8.82 32.0 ± 8.5 32.1 ± 8.95 -
    Years Since Multiple Sclerosis Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    4.6 ± 5.12 2.8 ± 4.98 3.6 ± 4.43 3.63 ± 4.613 3.50 ± 4.207 3.97 ± 5.171 -
    Expanded Disability Status Scale (EDSS) Score at Baseline
    The EDSS is a scale for assessing disability in 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, ambulation and other functions). Based on scores in these 8 functional systems, an overall score ranging from 0 (normal) to 10 (death due to MS) was assigned. Participants with EDSS scores of 0.0 to 4.5 are fully ambulatory; patients with EDSS scores of 5.0 to 9.5 have impaired ambulation.
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.85 ± 1.273 2.94 ± 1.287 2.86 ± 1.213 2.49 ± 1.158 2.48 ± 1.166 2.55 ± 1.145 -
    Years Since MS Symptom Onset
    Units: Years
        arithmetic mean (standard deviation)
    8.1 ± 6.97 6.0 ± 6.41 6.2 ± 5.79 6.36 ± 6.065 6.23 ± 5.547 6.92 ± 6.201 -
    Number of Relapses Within the Last 12 months Prior to Screening
    Units: Relapses
        arithmetic mean (standard deviation)
    1.3 ± 0.64 1.5 ± 1.18 1.3 ± 0.73 1.3 ± 0.58 1.4 ± 0.64 1.3 ± 0.60 -
    Number of Gadolinium Enhancing (GdE) Lesions at Baseline
    Units: Lesions
        arithmetic mean (standard deviation)
    1.4 ± 3.36 0.9 ± 1.42 1.3 ± 2.75 1.8 ± 3.54 1.8 ± 3.62 1.6 ± 3.78 -
    Subject analysis sets

    Subject analysis set title
    Placebo (Part A Core)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received placebo capsules (identical in appearance to RPC1063) by mouth (PO) daily during the 24-week placebo-controlled phase.

    Subject analysis set title
    Ozanimod 0.5 mg (Part A Core)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase

    Subject analysis set title
    Ozanimod 1 mg (Part A Core)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase.

    Subject analysis set title
    Interferon Beta-1a (IFN β-1a) (Part B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

    Subject analysis set title
    Ozanimod 0.5 mg (Part B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

    Subject analysis set title
    Ozanimod 1 mg (Part B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 1 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

    Subject analysis sets values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core) Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects
    88
    87
    83
    441
    439
    433
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    88
    87
    83
    441
    439
    433
        From 65-84 years
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.0 ± 8.67
    38.1 ± 9.17
    38.4 ± 40.0
    35.1 ± 9.07
    35.4 ± 8.82
    36.0 ± 8.89
    Sex: Female, Male
    Units: Subjects
        Female
    62
    60
    59
    304
    287
    291
        Male
    26
    27
    27
    137
    151
    142
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    87
    84
    83
    432
    431
    428
        Black|
    1
    2
    0
    7
    6
    5
        Asian|
    0
    1
    0
    1
    0
    0
        Other
    0
    0
    0
    1
    2
    0
    Region, Category
    Units: Subjects
        North America
    4
    4
    4
    16
    16
    16
        Western Europe
    6
    4
    3
    40
    40
    36
        Eastern Europe
    78
    79
    76
    379
    378
    374
        South Africa
    0
    0
    0
    6
    5
    7
        Missing
    0
    0
    0
    0
    0
    0
    Age at Multiple Sclerosis Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    33.9 ± 8.30
    34.8 ± 10.01
    34.4 ± 9.51
    31.6 ± 8.82
    32.0 ± 8.5
    32.1 ± 8.95
    Years Since Multiple Sclerosis Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    4.6 ± 5.12
    2.8 ± 4.98
    3.6 ± 4.43
    3.63 ± 4.613
    3.50 ± 4.207
    3.97 ± 5.171
    Expanded Disability Status Scale (EDSS) Score at Baseline
    The EDSS is a scale for assessing disability in 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, ambulation and other functions). Based on scores in these 8 functional systems, an overall score ranging from 0 (normal) to 10 (death due to MS) was assigned. Participants with EDSS scores of 0.0 to 4.5 are fully ambulatory; patients with EDSS scores of 5.0 to 9.5 have impaired ambulation.
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.85 ± 1.273
    2.94 ± 1.287
    2.86 ± 1.213
    2.49 ± 1.158
    2.48 ± 1.166
    2.55 ± 1.145
    Years Since MS Symptom Onset
    Units: Years
        arithmetic mean (standard deviation)
    8.1 ± 6.97
    6.0 ± 6.41
    6.2 ± 5.79
    6.36 ± 6.065
    6.23 ± 5.547
    6.92 ± 6.201
    Number of Relapses Within the Last 12 months Prior to Screening
    Units: Relapses
        arithmetic mean (standard deviation)
    1.3 ± 0.64
    1.5 ± 1.18
    1.3 ± 0.73
    1.3 ± 0.58
    1.4 ± 0.64
    1.3 ± 0.60
    Number of Gadolinium Enhancing (GdE) Lesions at Baseline
    Units: Lesions
        arithmetic mean (standard deviation)
    1.4 ± 3.36
    0.9 ± 1.42
    1.3 ± 2.75
    1.8 ± 3.54
    1.8 ± 3.62
    1.6 ± 3.78

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Part A Core)
    Reporting group description
    Participants received placebo capsules (identical in appearance to ozanimod) by mouth (PO) daily during the 24-week placebo-controlled phase. Participants were given the option to enter into a blinded extension phase and were re-randomized to receive ozanimod 0.5 mg or 1mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Ozanimod 0.5 mg (Part A Core)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 0.5 mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Ozanimod 1 mg (Part A Core)
    Reporting group description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. These participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Interferon Beta-1a (IFN β-1a) (Part B)
    Reporting group description
    Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

    Reporting group title
    Ozanimod 0.5 mg (Part B)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

    Reporting group title
    Ozanimod 1 mg (Part B)
    Reporting group description
    Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months
    Reporting group title
    Placebo-Ozanimod 0.5 mg (Part A Extension)
    Reporting group description
    Participants initially randomized to placebo capsules PO daily during the 24-week placebo controlled treatment phase were re-randomized to receive ozanimod 0.5 mg capsules during the optional blinded extension period for an additional 96 weeks of treatment.

    Reporting group title
    Ozanimod 0.5 mg - 0.5 mg (Part A Extension)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 0.5 mg capsules PO daily for an additional 96 weeks of treatment.

    Reporting group title
    Placebo-Ozanimod 1 mg (Part A Extension)
    Reporting group description
    Participants initially randomized to placebo capsules PO daily during the 24-week placebo controlled treatment phase were re-randomized to receive ozanimod 1 mg capsules during the optional blinded extension period for an additional 96 weeks of treatment.

    Reporting group title
    Ozanimod 1 mg - 1mg (Part A Extension)
    Reporting group description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.

    Subject analysis set title
    Placebo (Part A Core)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received placebo capsules (identical in appearance to RPC1063) by mouth (PO) daily during the 24-week placebo-controlled phase.

    Subject analysis set title
    Ozanimod 0.5 mg (Part A Core)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase

    Subject analysis set title
    Ozanimod 1 mg (Part A Core)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase.

    Subject analysis set title
    Interferon Beta-1a (IFN β-1a) (Part B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

    Subject analysis set title
    Ozanimod 0.5 mg (Part B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

    Subject analysis set title
    Ozanimod 1 mg (Part B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received ozanimod 1 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

    Primary: Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24

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    End point title
    Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24 [1]
    End point description
    The number of gadolinium-enhancing lesions per MRI scan was measured as the total number of Gd-enhancing lesions that occurred from Week 12 to Week 24. Missing GdE data values were imputed using the last valid non-missing, post-baseline observation which was carried forward if the participant was only missing 1 or 2 consecutive post-baseline scans. If there were no post-baseline values to be carried forward or if the participant was missing more than 2 consecutive scans then the mean number of lesions from participants in the same treatment group at the same visit was used as the imputed value. The ITT population is defined as all randomized participants who received at least 1 dose of study drug; participants analyzed according to the treatment they were randomized to receive and not according to what they actually received, if different. Includes participants with non-missing MRI results and included to the analysis population.
    End point type
    Primary
    End point timeframe
    From Week 12 to Week 24
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24 statistical analysis was performed in the study for Part A only.
    End point values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core)
    Number of subjects analysed
    88
    87
    83
    Units: Brain Lesions
        arithmetic mean (standard deviation)
    11.1 ± 29.86
    1.5 ± 3.68
    1.5 ± 3.44
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001 [3]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.
    [3] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.04944 level of significance.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    < 0.0001 [5]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline
    [5] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.04944 level of significance

    Primary: Part B: Adjusted Annualized Relapse Rate (ARR) at the End of Month 24

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    End point title
    Part B: Adjusted Annualized Relapse Rate (ARR) at the End of Month 24
    End point description
    The relapse rate was based on confirmed relapses. Relapses that met the clinical criteria for a relapse and were accompanied by objective neurological worsening (based upon EDSS evaluated by a blinded EDSS evaluator) were confirmed by a treating investigator. A relapse was defined as new or recurrent neurological symptoms preceded by a relatively stable or improving neurological state of at least 30 days (less than 30 days following the onset of a protocol-defined relapse was considered part of the same relapse). Symptoms must have persisted for >24 hours and should not be attributable to confounding clinical factors. The relapse rate (per person) was calculated as the number of relapses for an individual patient divided by the number of days that patient participated in the study, and multiplied by 365.25. The adjusted ARR was performed using a Poisson regression model. The ITT population included all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    At the end of month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    441
    439
    433
    Units: Relapses/Year
        least squares mean (confidence interval 95%)
    0.276 (0.234 to 0.324)
    0.218 (0.183 to 0.259)
    0.172 (0.142 to 0.208)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    < 0.0001 [7]
    Method
    Poisson regression model
    Parameter type
    Rate Ratio
    Point estimate
    0.623
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.506
         upper limit
    0.768
    Notes
    [6] - To account for multiple comparisons, each of the 2 treatment (0.5 mg and 1 mg ozanimod vs IFN) comparisons was tested at the alpha = 0.025 level.
    [7] - Adjusted for region, age at baseline and the baseline number of gadolinium-enhancing (GdE) lesions, and included the natural log transformation of time on study as an offset term.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.0167 [9]
    Method
    Poisson Regression Model
    Parameter type
    Rate Ratio
    Point estimate
    0.791
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.652
         upper limit
    0.958
    Notes
    [8] - To account for multiple comparisons, each of the 2 treatment (0.5 mg and 1 mg ozanimod vs IFN) comparisons was tested at the alpha = 0.025 level.
    [9] - Adjusted for region, age at baseline and the baseline number of gadolinium-enhancing (GdE) lesions, and included the natural log transformation of time on study as an offset term.

    Secondary: Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24

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    End point title
    Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24 [10]
    End point description
    The number of Gd-enhancing lesions per MRI scan was measured as the total number of Gd-enhancing lesions that occurred at Week 24. The ITT population is defined as all randomized participants who received at least 1 dose of study drug. Missing GdE data values were imputed using the mean number of lesions from participants in the same treatment group at the same visit.
    End point type
    Secondary
    End point timeframe
    At Week 24
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24 statistical analysis was performed in the study for Part A only
    End point values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core)
    Number of subjects analysed
    88
    87
    83
    Units: Lesions
        arithmetic mean (standard deviation)
    3.2 ± 9.80
    0.3 ± 0.86
    0.2 ± 0.59
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.

    Secondary: Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24

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    End point title
    Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24 [13]
    End point description
    The number of new or enlarging hyperintense T2-weighted brain MRI lesions was based on the cumulative number of new or enlarging T2 lesions since baseline from Week 12 to Week 24. The ITT population is defined as all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 12 to Week 24
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24 statistical analysis was performed in the study for Part A only.
    End point values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core)
    Number of subjects analysed
    88
    87
    83
    Units: Brain Lesions
        arithmetic mean (standard deviation)
    9.0 ± 20.87
    1.4 ± 3.21
    0.8 ± 1.86
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.

    Secondary: Part A: Adjusted Annualized Relapse Rate (ARR) at Week 24

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    End point title
    Part A: Adjusted Annualized Relapse Rate (ARR) at Week 24 [16]
    End point description
    The relapse rate was based on confirmed relapses. Relapses that met the clinical criteria for a relapse and were accompanied by objective neurological worsening (based upon EDSS evaluated by an independent, blinded EDSS evaluator) were confirmed by the treating investigator. A relapse was defined as new or recurrent neurological symptoms preceded by a relatively stable or improving neurological state of at least 30 days (less than 30 days following the onset of a protocol-defined relapse was considered part of the same relapse). Symptoms must have persisted for >24 hours and should not be attributable to confounding clinical factors. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    At the End of Week 24
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part A: The Adjusted Annualized Relapse Rate (ARR) at Week 24 statistical analysis was performed in the study for Part A only.
    End point values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core)
    Number of subjects analysed
    88
    87
    83
    Units: Relapses/Year
        least squares mean (confidence interval 95%)
    0.50 (0.22 to 1.15)
    0.35 (0.15 to 0.82)
    0.24 (0.09 to 0.61)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0531 [17]
    Method
    Poisson regression model
    Parameter type
    Rate Ratio
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.22
         upper limit
    1.01
    Notes
    [17] - Adjusted for region, the number of relapses within 24 months prior to the study, and the presence of GdE lesions as baseline.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2714 [18]
    Method
    Poisson regression model
    Parameter type
    Rate Ratio
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    1.34
    Notes
    [18] - Adjusted for region, the number of relapses within 24 months prior to the study, and the presence of GdE lesions as baseline.

    Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Treatment Phase

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    End point title
    Part A: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Treatment Phase [19]
    End point description
    A TEAE was defined as any event with an onset date on or after first dose date, or any ongoing event on the first dose date that worsened in severity after first dose date to the time that the participant concluded or was terminated in the study. AEs included, but were not limited to a worsening or change in nature, severity, or frequency of conditions present at the start of the study, patient deterioration due to primary illness, intercurrent illness and drug interaction. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose results in death, was life threatening, required inpatient hospitalization or prolongation of existing inpatient hospitalization, was a congenital abnormality or birth defect, or resulted in significant disability/incapacity. Adverse events were classified by severity (mild, moderate and severe).
    End point type
    Secondary
    End point timeframe
    Day 1 of first dose of study drug to the time that the participant concluded or was terminated in the study. The maximum duration of exposure in the ozanimod 0.5 mg arm was 189 days and 190 days in the ozanimod 1 mg arm.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses were performed for the TEAE during the placebo-controlled period in 201 Part A.
    End point values
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1 mg (Part A Core)
    Number of subjects analysed
    88
    87
    83
    Units: Participants
        Any TEAE
    52
    57
    47
        Any Moderate or Severe TEAE
    23
    23
    13
        Any Severe TEAE
    1
    2
    1
        Any Possible, Probable or Related TEAE
    11
    19
    15
        Any Related TEAE
    1
    1
    0
        Any Serious TEAE|
    0
    3
    0
        Any Related Serious TEAE
    0
    0
    0
        Any TEAE Leading to Discontinuation of Drug
    0
    0
    0
        Any Death Related to RPC1063
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events During the Placebo Controlled and Blinded Extension Phase

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    End point title
    Part A: Number of Participants With Treatment Emergent Adverse Events During the Placebo Controlled and Blinded Extension Phase
    End point description
    A TEAE was defined as any adverse event with a start date on or after the date of first dose of study drug up through the first dose of study drug in the open-label extension for those who continued into the open-label extension. AEs included, but were not limited to a worsening or change in nature, severity, or frequency of conditions present at the tart of the study, patient deterioration due to primary illness, intercurrent illness and drug interaction. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose results in death, was life threatening, required inpatient hospitalization or prolongation of existing inpatient hospitalization, was a congenital abnormality or birth defect, or resulted in significant disability/incapacity. Adverse events were classified by severity (mild, moderate and severe).
    End point type
    Secondary
    End point timeframe
    Day 1 of first dose of study drug to the time that the participant concluded or was terminated in the study; maximum duration of exposure for PBO-Ozanimod 0.5 mg was 30.82 months, 37.04 months for Ozanimod 0.5 mg-0.5mg, 33.21 months for PBO-Ozanimod 1mg.
    End point values
    Placebo-Ozanimod 0.5 mg (Part A Extension) Ozanimod 0.5 mg - 0.5 mg (Part A Extension) Placebo-Ozanimod 1 mg (Part A Extension) Ozanimod 1 mg - 1mg (Part A Extension)
    Number of subjects analysed
    41
    85
    42
    81
    Units: Participants
        Any TEAE
    26
    73
    32
    61
        Any Moderate or Severe TEAE
    17
    42
    18
    35
        Any Severe TEAE
    2
    4
    1
    2
        Any Possible, Probable or Related TEAE
    11
    30
    12
    26
        Any Related TEAE
    2
    3
    1
    3
        Any Serious TEAE|
    2
    10
    3
    6
        Any Related Serious TEAE
    0
    0
    0
    0
        Any TEAE Leading to Discontinuation of Ozanimod
    2
    1
    1
    0
        Any Death Related to Ozanimod
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Part B: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging Lesions Per Scan Over 24 Months

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    End point title
    Part B: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging Lesions Per Scan Over 24 Months
    End point description
    The adjusted mean number of new or enlarging hyperintense T2-weighted brain MRI lesions was based on the cumulative number of new or enlarging T2 lesions since baseline over 24 months. Adjusted mean (95% CI) over 24 months was calculated as the model-based adjusted mean (95% CI) per scan multiplied by the mean number of available MRI scans over 24 months. The ITT population included all randomized participants who received at least 1 dose of study drug. Includes participants with non-missing MRI results.
    End point type
    Secondary
    End point timeframe
    24 month treatment period; MRI scans performed at baseline, at month 12 and 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    336
    329
    327
    Units: Lesions/Scan
        least squares mean (confidence interval 95%)
    3.183 (2.640 to 3.838)
    2.092 (1.741 to 2.514)
    1.835 (1.523 to 2.211)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    P-value
    < 0.0001 [21]
    Method
    Negative Binomial Regression Model
    Parameter type
    Rate Ratio
    Point estimate
    0.576
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.465
         upper limit
    0.714
    Notes
    [20] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level
    [21] - Adjusted for region, age at baseline, and baseline GdE lesions; included the natural log transformation of available MRI scans as an offset term.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    < 0.0001 [23]
    Method
    Negative binomial regression model
    Parameter type
    Rate Ratio
    Point estimate
    0.657
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.531
         upper limit
    0.813
    Notes
    [22] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level
    [23] - Adjusted for region, age at baseline, and baseline GdE lesions; included the natural log transformation of available MRI scans as an offset term.

    Secondary: Part B: Adjusted Mean Number of Gadolinium Enhancing Brain Lesions per Scan at Month 24

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    End point title
    Part B: Adjusted Mean Number of Gadolinium Enhancing Brain Lesions per Scan at Month 24
    End point description
    The number of GdE T1-lesions per MRI scan was measured as the total number of Gd- enhancing T1-lesions on the 24-month MRI scan. The ITT population consisted of all randomized participants who received at least 1 dose of study medication. Includes participants with non-missing MRI results.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    336
    329
    237
    Units: Lesions
        least squares mean (confidence interval 95%)
    0.373 (0.256 to 0.543)
    0.197 (0.131 to 0.296)
    0.176 (0.116 to 0.266)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    < 0.0006 [25]
    Method
    Negative Binomial Regression Model
    Parameter type
    Rate Ratio
    Point estimate
    0.471
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.306
         upper limit
    0.725
    Notes
    [24] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
    [25] - Adjusted for region, age at baseline, and baseline GdE lesions. Included the natural log transformation of the number available MRI scans at 24 month was used as an offset term.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    < 0.003 [27]
    Method
    Negative binomial regression model
    Parameter type
    Rate Ratio
    Point estimate
    0.528
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.346
         upper limit
    0.805
    Notes
    [26] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
    [27] - Adjusted for region, age at baseline, and baseline GdE lesions. Included the natural log transformation of the number available MRI scans at 24 month was used as an offset term.

    Secondary: Part B: Time to Onset of Disability Progression Confirmed After 3 Months

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    End point title
    Part B: Time to Onset of Disability Progression Confirmed After 3 Months
    End point description
    The Expanded Disability Status Scale (EDSS) is an ordinal scale in half-point increments that quantifies disability progression in MS patients over time. It assesses seven functional (neurologic) systems and ambulation scores that are combined to determine the EDSS score ranging from 1 (normal) to 10 (death due to MS) with higher scores indicating greater disability. The 7 Functional System (FS) scales are: pyramidal, cerebellar, brainstem, sensory, bowel or bladder, visual, and cerebral. Disability progression was defined by a sustained worsening (increase) in EDSS of 1.0 points or more from baseline, confirmed after 3 months. Participants were censored if follow-up ended before a sustained progression occurred, whether due to the patient completing study, withdrawing from the study, or due to the cutoff of data collection for the analysis. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    For the duration of the entire treatment period; 24 months
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    441 [28]
    439 [29]
    433 [30]
    Units: days
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [28] - 99999 = data was not estimable as there were insufficient disability events at 3 months
    [29] - 99999 = data was not estimable as there were insufficient disability events at 3 months
    [30] - 99999 = data was not estimable as there were insufficient disability events at 3 months
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    = 0.8224 [32]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.711
         upper limit
    1.537
    Notes
    [31] - Cox proportional hazard model with factors for treatment group
    [32] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.2849 [34]
    Method
    Cox proportional hazard model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.798
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.528
         upper limit
    1.206
    Notes
    [33] - Cox proportional hazard model with factors for treatment group.
    [34] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.

    Secondary: Part B: Time to Onset of Disability Progression Confirmed After 6 months

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    End point title
    Part B: Time to Onset of Disability Progression Confirmed After 6 months
    End point description
    The Expanded Disability Status Scale (EDSS) is an ordinal scale in half-point increments that quantifies disability progression in MS patients over time. It assesses seven functional (neurologic) systems and ambulation scores that are combined to determine the EDSS score ranging from 1 (normal) to 10 (death due to MS) with higher scores indicating greater disability. The 7 Functional System (FS) scales are: pyramidal, cerebellar, brainstem, sensory, bowel or bladder, visual, and cerebral. Disability progression was defined by a sustained worsening (increase) in EDSS of 1.0 points or more from baseline, confirmed after 6 months. Participants were censored if follow-up ended before a sustained progression occurred, whether due to the patient completing study, withdrawing from the study, or due to the cutoff of data collection for the analysis. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    For the duration of the entire treatment period; 24 months
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    441 [35]
    439 [36]
    433 [37]
    Units: days
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [35] - 99999 = Not Estimable as there were insufficient disability events at 6 months
    [36] - 99999 = Not Estimable as there were insufficient disability events at 6 months
    [37] - 99999 = Not Estimable as there were insufficient disability events at 6 months
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    = 0.1353 [39]
    Method
    Cox proportional hazard model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.435
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.893
         upper limit
    2.305
    Notes
    [38] - Cox proportional hazard model with factors for treatment group.
    [39] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    P-value
    = 0.7154 [41]
    Method
    Cox proportional hazard model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.098
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.664
         upper limit
    1.815
    Notes
    [40] - Cox proportional hazard model with factors for treatment group.
    [41] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.

    Secondary: Part B: Percentage of Participants Who Were Gadolinium Enhancing Lesion-Free at Month 24

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    End point title
    Part B: Percentage of Participants Who Were Gadolinium Enhancing Lesion-Free at Month 24
    End point description
    Participants were considered lesion free at Month 24 if they did not show evidence of GdE lesions at the month 24 MRI scan. The ITT population included all randomized participants who received at least 1 dose of study drug; analysis included non-responder imputation that being as not lesion-free.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    441
    439
    433
    Units: Percentage of Participants
        number (confidence interval 95%)
    56.2 (51.6 to 60.9)
    63.3 (58.8 to 67.8)
    65.6 (61.1 to 70.1)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0047 [42]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Percentage
    Point estimate
    9.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.9
         upper limit
    15.8
    Notes
    [42] - Stratified by region (Eastern Europe vs Rest of the World) and EDSS category per Interactive Voice Response System (IVRS).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.032 [43]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Percentage
    Point estimate
    7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    13.6
    Notes
    [43] - Stratified by region (Eastern Europe vs Rest of the World) and EDSS category per Interactive Voice Response System (IVRS).

    Secondary: Part B: Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24

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    End point title
    Part B: Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24
    End point description
    Participants were considered T2 lesion free at Month 24 if they did not show evidence of a relapse in T2 lesions at month 24. The ITT population consisted of all randomized participants who received at least 1 dose of study medication; participants who were missing the Month 24 MRI data were considered non-responders, ie, as not being lesion-free.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    441
    439
    433
    Units: Percentage of Participants
        number (confidence interval 95%)
    18.4 (14.8 to 22.0)
    23.5 (19.5 to 27.4)
    23.8 (19.8 to 27.8)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0466 [44]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Percentage
    Point estimate
    5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    10.8
    Notes
    [44] - Based on the Cochran-Mantel-Haenszel test stratified by region (Eastern Europe vs. rest of the world) and EDSS category per IVRS.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0581 [45]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Percentage
    Point estimate
    5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    10.5
    Notes
    [45] - Based on the Cochran-Mantel-Haenszel test stratified by region (Eastern Europe vs. rest of the world) and EDSS category per IVRS.

    Secondary: Part B: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 24

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    End point title
    Part B: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 24
    End point description
    Atrophy or loss in brain volume was measured by MRI scan from baseline to month 24. Observed values for the ITT Population; included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    439
    437
    432
    Units: Percent Change in Brain Volume Loss
    median (full range (min-max))
        Baseline
    1455.662 (1208.191 to 1667.703)
    1452.878 (1171.858 to 1663.032)
    1445.978 (1190.494 to 1660.718)
        Percent Change from Baseline to Month 24
    -0.940 (-5.33 to 1.44)
    -0.710 (-5.21 to 1.36)
    -0.690 (-5.65 to 0.85)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    871
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [46]
    Method
    Rank Ancova
    Confidence interval
    Notes
    [46] - Based on the analysis of covariance model, adjusted for region, and EDSS category per IVRS, with the dependent variable as the residual of the rank of brain volume at Baseline (Month 12 brain volume for Percent Change from Month 12 to Month 24).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    876
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [47]
    Method
    Rank Ancova
    Confidence interval
    Notes
    [47] - Based on the analysis of covariance model, adjusted for region, and EDSS category per IVRS, with the dependent variable as the residual of the rank of brain volume at Baseline (Month 12 brain volume for Percent Change from Month 12 to Month 24).

    Secondary: Part B: Change in Multiple Sclerosis Functional Composite (MSFC) Score from Baseline to Month 24 (including the Low-Contrast Letter Acuity test [LCLA] Measurement of Visual Function as a Component)

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    End point title
    Part B: Change in Multiple Sclerosis Functional Composite (MSFC) Score from Baseline to Month 24 (including the Low-Contrast Letter Acuity test [LCLA] Measurement of Visual Function as a Component)
    End point description
    The MSFC-LCLA is a battery of tests including 4 scales: • The Timed 25-Foot Walk is an ambulation measure of walking 25 feet with time taken recorded in seconds • The 9-Hole Peg Test is a quantitative measure of upper extremity (arm and hand) function • The Symbol Digit Modalities Test is a measure of executive cognitive function that assesses processing speed, flexibility, and calculation ability • LCLA used a standardized set of charts to assess low contrast visual acuity Z-scores were calculated for the MSFC for each component and averaged to create an overall composite Z -score. A z-score represents the number of standard deviations a patient’s test result is higher (z >0) or lower (z <0) than the average test result (z = 0) of the reference population. A score of +1 indicates that, on average, an individual scored 1 standard deviation better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    437
    435
    428
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.052 ± 0.601
    0.036 ± 0.440
    -0.010 ± 0.622
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    865
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.248 [48]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.116
    Notes
    [48] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS and baseline MSFC Z-score
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    872
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0123 [49]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.093
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.165
    Notes
    [49] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and baseline MSFC Z-score

    Secondary: Part B: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 24

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    End point title
    Part B: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 24
    End point description
    The MSQOL-54 is a multidimensional health-related QOL measure that combines both generic and MS-specific items into a single instrument. The instrument generates 12 subscales along with two summary scores, and two additional single-item measures. The subscales are: physical function, role limitations-physical, role limitations-emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, and sexual function. The summary scores are the physical health composite summary and the mental health composite summary. The change for the summary scores for the physical health and mental health composite, plus statistical analysis are reported. Each domain has a range from 0 to 100 where higher means better. The ITT population consisted of all randomized participants who received at least 1 dose of study drug. Missing data were imputed using a mixed effects regression model.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    441
    439
    433
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Health Composite Summary
    -1.526 ± 12.319
    0.609 ± 12.315
    0.209 ± 12.321
        Mental Health Composite Summary
    -1.831 ± 16.422
    -1.182 ± 14.379
    -1.517 ± 15.544
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis of Physical Health Composite Summary Month 24
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0988 [50]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.345
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.252
         upper limit
    2.943
    Notes
    [50] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis of Physical Health Composite Summary Month 24
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0228 [51]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.849
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.258
         upper limit
    3.44
    Notes
    [51] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis of Mental Health Composite Summary Month 24
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6997 [52]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.553
         upper limit
    2.313
    Notes
    [52] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Analysis of Mental Health Composite Summary Month 24
    Comparison groups
    Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5501 [53]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.587
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.339
         upper limit
    2.513
    Notes
    [53] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.

    Secondary: Part B: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During Part B

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    End point title
    Part B: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During Part B
    End point description
    An AE is any untoward medical occurrence that does not necessarily have a causal relationship with the investigational product (IP). An AE can be any unfavorable or unintended sign, including an abnormal laboratory finding, symptom or disease temporally associated with the use of an IP whether or not considered related to the IP. A TEAE = an AE with a start date on or after the date of first dose of IP to the time that the participant concluded or was terminated in the study. A serious AE (SAE) is any untoward medical occurrence or effect that results in death, is life- threatening, requires hospitalization or prolongation of existing inpatient hospitalization. The investigator assessed the severity of AEs as mild, moderate, or severe. Safety Population consisted of all participants who received at least 1 dose of randomized study medication.
    End point type
    Secondary
    End point timeframe
    Day 1 of first dose of study drug to the time that the participant concluded or was terminated in the study; the overall maximum study duration of exposure to IFN = 24.46 months, 25.05 months for ozanimod 0.5 mg and 25.05 months for ozanimod 1 mg.
    End point values
    Interferon Beta-1a (IFN β-1a) (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1 mg (Part B)
    Number of subjects analysed
    440
    439
    434
    Units: Participants
    number (not applicable)
        Any TEAE
    365
    326
    324
        Any Moderate or Severe TEAE
    235
    169
    170
        Any Severe TEAE
    19
    19
    15
        Any Suspected TEAE
    113
    104
    115
        Any Related TEAE
    30
    12
    19
        Any Serious TEAE
    28
    31
    28
        Any Suspected Serious TEAE
    3
    4
    4
        Any Related Serious TEAE
    0
    1
    1
        Any TEAE Leading to Stopping of Study Drug
    18
    14
    13
        Any TEAE Leading to Study Withdrawal
    20
    13
    13
        Any Death
    0
    1
    1
        Any Death on Study
    0
    1
    0
    No statistical analyses for this end point

    Post-hoc: Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period

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    End point title
    Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period
    End point description
    Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period.
    End point type
    Post-hoc
    End point timeframe
    From Week 24 to Week 120
    End point values
    Placebo-Ozanimod 0.5 mg (Part A Extension) Ozanimod 0.5 mg - 0.5 mg (Part A Extension) Placebo-Ozanimod 1 mg (Part A Extension) Ozanimod 1 mg - 1mg (Part A Extension)
    Number of subjects analysed
    41 [54]
    85 [55]
    42 [56]
    81 [57]
    Units: Lesions
    geometric mean (standard error)
        Week 24
    4.5 ± 13.02
    0.4 ± 1.28
    1.9 ± 5.93
    0.2 ± 0.60
        Week 72
    0.4 ± 1.95
    0.4 ± 1.60
    0.1 ± 0.28
    0.2 ± 0.56
        Week 120
    0.1 ± 0.46
    0.4 ± 1.49
    0.1 ± 0.37
    0.2 ± 0.51
    Notes
    [54] - Week 72 = 38 Week 120 N = 37
    [55] - Week 72 N = 76 Week 120 N = 72
    [56] - Week 72 N = 37 Week 120 N = 36
    [57] - Week 72 N = 79 Week 120 N = 74
    No statistical analyses for this end point

    Post-hoc: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions In the Blinded Extension Period

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    End point title
    The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions In the Blinded Extension Period
    End point description
    The number of new or enlarging hyperintense T2-weighted brain MRI lesions was based on the cumulative number of new or enlarging T2 lesions on MRI
    End point type
    Post-hoc
    End point timeframe
    From Week 0 to Week 24 of Part A of the 201A Core Period and Year 1 and 2 of the Extension Period
    End point values
    Placebo-Ozanimod 0.5 mg (Part A Extension) Ozanimod 0.5 mg - 0.5 mg (Part A Extension) Placebo-Ozanimod 1 mg (Part A Extension) Ozanimod 1 mg - 1mg (Part A Extension)
    Number of subjects analysed
    41 [58]
    85 [59]
    42 [60]
    81 [61]
    Units: lesions
    geometric mean (standard error)
        ROC01-201A Core (Weeks 0 to 24)
    10.8 ± 3.58
    1.4 ± 0.35
    7.3 ± 3.07
    0.9 ± 0.21
        Year 1 In Extension Study
    4.3 ± 1.99
    2.8 ± 0.72
    1.5 ± 0.39
    1.9 ± 0.84
        Year 2 In Extension Study
    3.2 ± 1.31
    2.3 ± 0.61
    1.9 ± 0.48
    0.7 ± 0.16
    Notes
    [58] - Year 1 N = 38 Year 2 N = 37
    [59] - Year 1 N = 76 Year 2 N = 71
    [60] - Year 1 N = 37 Year 2 N = 36
    [61] - Year 1 N = 79 Year 2 N = 74
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 of study drug to the date that the participant concluded or was terminated in the study. AEs are reported for Part A placebo-controlled and extension periods followed by Part B for 2 years.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo (Part A Core)
    Reporting group description
    Participants received placebo capsules (identical in appearance to ozanimod) PO daily during the placebo-controlled phase (Weeks 0-24).

    Reporting group title
    Ozanimod 0.5 mg (Part A Core)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily during the placebo-controlled phase (Weeks 0 to 24).

    Reporting group title
    Ozanimod 1.0 mg (Part A Core)
    Reporting group description
    Participants received ozanimod 1 mg capsules PO daily during the placebo-controlled phase (Weeks 0 to 24).

    Reporting group title
    Ozanimod 0.5 mg (Part A Extension)
    Reporting group description
    Participants received ozanimod 0.5 mg capsules PO daily during the blinded extension phase (Weeks 25 to 96).

    Reporting group title
    Ozanimod 1.0 mg (Part A Extension)
    Reporting group description
    Participants received ozanimod 1 mg capsules PO daily during the blinded extension phase (Weeks 25 to 96).

    Reporting group title
    Interferon ß-1a 30 µg (Part B)
    Reporting group description
    Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.

    Reporting group title
    Ozanimod 0.5 mg (Part B)
    Reporting group description
    Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.

    Reporting group title
    Ozanimod 1.0 mg (Part B)
    Reporting group description
    Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.

    Serious adverse events
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1.0 mg (Part A Core) Ozanimod 0.5 mg (Part A Extension) Ozanimod 1.0 mg (Part A Extension) Interferon ß-1a 30 µg (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1.0 mg (Part B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 87 (3.45%)
    0 / 83 (0.00%)
    10 / 126 (7.94%)
    9 / 123 (7.32%)
    28 / 440 (6.36%)
    31 / 439 (7.06%)
    28 / 434 (6.45%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast Cancer
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive Breast Carcinoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma In Situ
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medulloblastoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Fibroma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal Growth Restriction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Placental Polyp
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vanishing Twin Syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatoform Disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast Cyst
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Polyp
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional Uterine Bleeding
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Cervical Squamous Metaplasia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Polyp
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carbon Monoxide Poisoning
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Comminuted Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    2 / 439 (0.46%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Acoustic Neuritis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autonomic Nervous System Imbalance
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cauda Equina Syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central Nervous System Lesion
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Radiculopathy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    1 / 439 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre Syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic Neuritis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech Disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Keratoconus
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Wall Haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable Bowel Syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Urinary
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal Colic
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral Stenosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperplastic Cholecystopathy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Ulcer
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stasis Dermatitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    1 / 123 (0.81%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute Hepatitis B
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    2 / 440 (0.45%)
    1 / 439 (0.23%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    1 / 439 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis Infectious
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    1 / 126 (0.79%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    1 / 440 (0.23%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Part A Core) Ozanimod 0.5 mg (Part A Core) Ozanimod 1.0 mg (Part A Core) Ozanimod 0.5 mg (Part A Extension) Ozanimod 1.0 mg (Part A Extension) Interferon ß-1a 30 µg (Part B) Ozanimod 0.5 mg (Part B) Ozanimod 1.0 mg (Part B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 88 (27.27%)
    24 / 87 (27.59%)
    10 / 83 (12.05%)
    52 / 126 (41.27%)
    43 / 123 (34.96%)
    275 / 440 (62.50%)
    185 / 439 (42.14%)
    199 / 434 (45.85%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 87 (1.15%)
    2 / 83 (2.41%)
    8 / 126 (6.35%)
    2 / 123 (1.63%)
    14 / 440 (3.18%)
    20 / 439 (4.56%)
    24 / 434 (5.53%)
         occurrences all number
    1
    1
    2
    8
    2
    14
    21
    24
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    27 / 440 (6.14%)
    27 / 439 (6.15%)
    30 / 434 (6.91%)
         occurrences all number
    0
    0
    0
    0
    0
    30
    29
    33
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 87 (3.45%)
    4 / 83 (4.82%)
    10 / 126 (7.94%)
    12 / 123 (9.76%)
    20 / 440 (4.55%)
    29 / 439 (6.61%)
    26 / 434 (5.99%)
         occurrences all number
    0
    4
    4
    17
    17
    28
    37
    35
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 87 (2.30%)
    5 / 83 (6.02%)
    11 / 126 (8.73%)
    8 / 123 (6.50%)
    9 / 440 (2.05%)
    16 / 439 (3.64%)
    25 / 434 (5.76%)
         occurrences all number
    0
    2
    5
    16
    10
    10
    20
    28
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 88 (9.09%)
    5 / 87 (5.75%)
    3 / 83 (3.61%)
    7 / 126 (5.56%)
    9 / 123 (7.32%)
    53 / 440 (12.05%)
    55 / 439 (12.53%)
    44 / 434 (10.14%)
         occurrences all number
    9
    11
    4
    14
    38
    138
    134
    187
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    215 / 440 (48.86%)
    26 / 439 (5.92%)
    27 / 434 (6.22%)
         occurrences all number
    0
    0
    0
    0
    0
    485
    38
    41
    Pyrexia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    27 / 440 (6.14%)
    12 / 439 (2.73%)
    10 / 434 (2.30%)
         occurrences all number
    0
    0
    0
    0
    0
    279
    12
    11
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    9 / 88 (10.23%)
    5 / 87 (5.75%)
    2 / 83 (2.41%)
    5 / 126 (3.97%)
    7 / 123 (5.69%)
    0 / 440 (0.00%)
    0 / 439 (0.00%)
    0 / 434 (0.00%)
         occurrences all number
    9
    5
    2
    5
    12
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 88 (13.64%)
    11 / 87 (12.64%)
    5 / 83 (6.02%)
    17 / 126 (13.49%)
    17 / 123 (13.82%)
    48 / 440 (10.91%)
    59 / 439 (13.44%)
    68 / 434 (15.67%)
         occurrences all number
    15
    11
    6
    37
    28
    77
    101
    100
    Pharyngitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 87 (0.00%)
    0 / 83 (0.00%)
    0 / 126 (0.00%)
    0 / 123 (0.00%)
    15 / 440 (3.41%)
    24 / 439 (5.47%)
    17 / 434 (3.92%)
         occurrences all number
    0
    0
    0
    0
    0
    16
    30
    23
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 88 (3.41%)
    4 / 87 (4.60%)
    3 / 83 (3.61%)
    20 / 126 (15.87%)
    11 / 123 (8.94%)
    37 / 440 (8.41%)
    36 / 439 (8.20%)
    34 / 434 (7.83%)
         occurrences all number
    3
    5
    4
    25
    15
    47
    47
    42
    Urinary Tract Infection
         subjects affected / exposed
    2 / 88 (2.27%)
    6 / 87 (6.90%)
    2 / 83 (2.41%)
    7 / 126 (5.56%)
    4 / 123 (3.25%)
    17 / 440 (3.86%)
    22 / 439 (5.01%)
    19 / 434 (4.38%)
         occurrences all number
    3
    6
    2
    11
    4
    21
    30
    25

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Sep 2012
    1. Modification of the primary objective in Part A from cumulative number of new GdE lesions to cumulative total number of GdE lesions. 2. Addition of a secondary objective in Part A to assess proportion of patients who are free of GdE lesions at Week 24. 3. Modification to treatment duration in Part B to 24 months for all patients. 4. Modification to inclusion/exclusion criteria to remove the exclusion of diagnosis with secondary progressive MS, and to require that patients must discontinue nonlymphocyte-depleting disease-modifying MS agents from signing of the informed consent until randomization. 5. Corresponding changes to study endpoints to accommodate modifications to study objectives in Part A. 6. Change in PK sampling schedule. 7. Addition of QuantiFERON Gold test as alternative to purified protein derivative test for TB screening. 8. Clarification of timing of procedures for Part A patients who elect to enter the blinded extension period after the Week 24 visit. 9. Clarification of unblinding procedure and timing of treatment for relapse. 10. Clarifications to the inclusion/exclusion criteria, study design, study procedures (throughout), Schedule of Assessment and corresponding footnotes, handling missed doses, matching placebo for IFN β-1, allowed/prohibited medications, clinical laboratory procedures, and notifications. Many of the remaining changes were related to consistency within the protocol, addition of clinical laboratory and corresponding contact details, project biostatistician personnel change, correction of typographical errors in the protocol and formatting throughout.
    31 Jul 2013
    1. Addition of exploratory endpoint to Part B: “the number of GdE brain MRI lesions at 24 months”. 2. Duration of the blinded extension of Part A was increased to at least 48 weeks for all patients (with total duration of Part A of at least 72 weeks, 24 weeks placebo-controlled period and at least 48 weeks blinded extension). 3. Clarifications that for patients continuing to the blinded extension, MRI scans would be performed annually after the Week 24 visit (at approximately Week 72) and/or at the End of-Study Visit. 4. Increase in sample size in Part B to 1200 patients (400 per arm) and modification of sample size justification accordingly. 5. Addition of section on “Considerations for Patients with Comorbid Conditions”. 6. Modification to withdrawal criteria and discontinuation of study medication. 7. Modifications to inclusion/exclusion criteria: Inclusion criterion no. 8 – clarification of sexual abstinence, Inclusion criterion no. 9 – clarification regarding proof of immunization for varicella zoster virus, Exclusion criterion no. 7 – specification of excluded cardiac conditions, Exclusion criterion no. 9 – specification of diabetes mellitus history, Addition of exclusion criterion no. 25 on excluded disease modifying therapies, Removal of exclusion criterion regarding B12 deficiency. 8. Modification to statistical methods including Clarification when the interim analysis of Part A would be done, and clarification of the Part B primary analysis per request of FDA. 9. Clarification that dermatological (skin) examination would be done by the investigator, not the dermatologist. 10. Other changes included clarifications to inclusion/exclusion criteria, study design, study procedures (throughout), Schedule of Assessment and corresponding footnotes, number of participating sites in Part A and B, study drug accountability, allowed and prohibited medications, and procedures in case of pregnancy.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26879276
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