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    Clinical Trial Results:
    A Phase 3, Multi-center, Randomized, Double-Blind, Double-Dummy, Active-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of RPC1063 Administered Orally to Relapsing Multiple Sclerosis Patients

    Summary
    EudraCT number
    		 2014-002320-27
    Trial protocol
    		 EE   PT   LV   SE   NL   BG   PL   ES   LT   HU   GB   HR  
    Global end of trial date
    22 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jan 2018
    First version publication date
    14 Jan 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RPC01-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02294058
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene International Sarle II
    Sponsor organisation address
    Rue des Moulins 4, 2108 Couvet, Switzerland,
    Public contact
    ClinicalTrialDisclosure, Celgene Corporation, +1 8882601599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    James Sheffield, Celgene Corporation, +1 619-371-1506, 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
    08 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether the clinical efficacy of RPC1063 is superior to interferon (IFN) β-1a (Avonex®) in reducing the rate of clinical relapses in patients with Relapsing Multiple Sclerosis (RMS).
    Protection of trial subjects
    Patient Confidentiality. 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
    03 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belarus: 123
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 12
    Country: Number of subjects enrolled
    Bulgaria: 16
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Estonia: 16
    Country: Number of subjects enrolled
    Georgia: 62
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Moldova, Republic of: 5
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Poland: 259
    Country: Number of subjects enrolled
    Portugal: 25
    Country: Number of subjects enrolled
    Romania: 29
    Country: Number of subjects enrolled
    Russian Federation: 272
    Country: Number of subjects enrolled
    Serbia: 65
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Ukraine: 382
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    1346
    EEA total number of subjects
    382
    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)
    1346
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in the United States, Eastern and Western Europe and New Zealand. 1346 participants were randomized from 152 sites in 20 countries,

    Pre-assignment
    Screening details
    		 Participant were randomized 1:1:1 ratio to one of three treatment groups. Randomization was stratified by baseline Expanded Disability Status Scale (EDSS) score (≤ 3.5, > 3.5) and country.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, 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, AEs, or laboratory changes. Each site had 2 investigators: a principal or treating investigator and a blinded evaluator who was the EDSS evaluator. The EDSS evaluator was responsible for the administering the EDSS and did not have access to other patient data prior to EDSS data when performing exams.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Interferon Beta-1a (IFN β-1a)
    Arm description
    		 Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally every day for at least one year.
    Arm type
    		 Active comparator

    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 physical appearance to Ozanimod) orally every day for one year

    Investigational medicinal product name
    Interferon Beta-1a (IFN β-1a)
    Investigational medicinal product code
    Other name
    Avonex
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IFN β-1a 30 μg IM weekly for one year

    Arm title
    		 Ozanimod 1 mg
    Arm description
    		 Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for at least one year.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    RPC-1063
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 1 mg capsules PO daily for one year

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular placebo injection (identical in physical appearance to IFN β-1a) every week for one year

    Arm title
    		 Ozanimod 0.5 mg
    Arm description
    		 Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for at least one year.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    RPC-1063
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod 0.5 mg capsules PO daily for one year

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular placebo injection (identical in physical appearance to IFN β-1a) every week for one year

    Number of subjects in period 1
    		Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Started
    448
    447
    451
    Completed
    412
    418
    425
    Not completed
    36
    29
    26
         Consent withdrawn by subject
    10
    13
    14
         Physician decision
    2
    -
    1
         Adverse event, non-fatal
    16
    13
    7
         Miscellaneous
    4
    1
    1
         Lost to follow-up
    1
    2
    -
         Lack of efficacy
    3
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Interferon Beta-1a (IFN β-1a)
    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 every day for at least one year.

    Reporting group title
    Ozanimod 1 mg
    Reporting group description
    		 Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for at least one year.

    Reporting group title
    Ozanimod 0.5 mg
    Reporting group description
    		 Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for at least one year.

    Reporting group values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg Total
    Number of subjects
    		 448 447 451 1346
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 448 447 451 1346
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.9 ± 9.11 34.8 ± 9.24 36.0 ± 9.43 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 300 283 311 894
        Male
    		 148 164 140 452
    Race
    Units: Subjects
        White
    		 447 446 447 1340
        Black
    		 0 0 2 2
        Asian
    		 0 1 1 2
        Other
    		 1 0 1 2
    Region, Category
    Units: Subjects
        Eastern Europe
    		 419 415 419 1253
        Rest of World
    		 29 32 32 93
    Age at MS Symptom Onset (years)
    Units: years
        arithmetic mean (standard deviation)
    		 29.5 ± 8.92 28.4 ± 8.42 29.3 ± 9.25 -
    Age at MS Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 32.7 ± 9.01 31.6 ± 8.81 32.7 ± 9.49 -
    Years Since MS Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 3.71 ± 4.361 3.60 ± 4.193 3.70 ± 4.518 -
    Expanded Disability Status Scale (EDSS) 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) is 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)
    		 2.62 ± 1.138 2.61 ± 1.160 2.65 ± 1.135 -
    Years Since MS Symptom Onset
    Units: years
        arithmetic mean (standard deviation)
    		 6.88 ± 5.877 7.16 ± 6.255 6.85 ± 6.449 -

    End points

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    End points reporting groups
    Reporting group title
    Interferon Beta-1a (IFN β-1a)
    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 every day for at least one year.

    Reporting group title
    Ozanimod 1 mg
    Reporting group description
    		 Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for at least one year.

    Reporting group title
    Ozanimod 0.5 mg
    Reporting group description
    		 Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for at least one year.

    Subject analysis set title
    IFN β-1a
    Subject analysis set type
    		 Safety analysis
    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 every day for one year.

    Subject analysis set title
    Ozanimod 1 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received Ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for one year.

    Subject analysis set title
    Ozanimod 0.5 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received Ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for one year.

    Primary: Adjusted Annualized Relapse Rate (ARR) During the Treatment Period

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    End point title
    		 Adjusted Annualized Relapse Rate (ARR) During the Treatment Period
    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 adjusted annualized relapse rate is based on the Poisson regression model, adjusted for region (Eastern Europe vs Rest of World), age at Baseline, and the baseline number of GdE lesions, and included the natural log transformation of time on study as an offset term. The Intent to Treat Population was included.
    End point type
    Primary
    End point timeframe
    Up to 2.5 years
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    448
    447
    451
    Units: Relapses/year
        least squares mean (confidence interval 95%)
    0.350 (0.279 to 0.440)
    0.181 (0.140 to 0.236)
    0.241 (0.188 to 0.308)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Poisson regression model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.518
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.405
         upper limit
    		 0.663
    Notes
    [1] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.025 level.
    [2] - Adjusted for region, baseline age, number of Gadolinium Enhancing (GdE) lesions and included the natural log transformation of time as an offset term.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0013 [4]
    Method
    		 Poisson Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.688
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.547
         upper limit
    		 0.864
    Notes
    [3] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.025 level.
    [4] - Adjusted for region, age at baseline, and the baseline number of GdE lesions, and included the natural log transformation of time on study as an offset term.

    Secondary: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging (MRI) Lesions per Scan over 12 months

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    End point title
    		 Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging (MRI) Lesions per Scan over 12 months
    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 over 12 months. Includes participants with non-missing MRI results and included to the analysis population.
    End point type
    Secondary
    End point timeframe
    12 month treatment period; MRI scans were assessed at months 6 and 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    382
    388
    397
    Units: T2 Lesions/scan
        least squares mean (confidence interval 95%)
    2.836 (2.331 to 3.451)
    1.465 (1.203 to 1.784)
    2.139 (1.777 to 2.575)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.517
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.427
         upper limit
    		 0.625
    Notes
    [5] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.05 level.
    [6] - Observed data, adjusted for region, age at baseline, and baseline number of GdE lesions. The natural log transformation of the number of available MRI scans over 12 months is used as an offset term.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    779
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0032 [8]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.754
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.625
         upper limit
    		 0.91
    Notes
    [7] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.05 level.
    [8] - Observed data, adjusted for region, age at baseline, and baseline number of GdE lesions. The natural log transformation of the number of available MRI scans over 12 months is used as an offset term.

    Secondary: Adjusted Mean Number of Gadolinium Enhancing (GdE) Brain MRI Lesions at Month 12

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    End point title
    		 Adjusted Mean Number of Gadolinium Enhancing (GdE) Brain MRI Lesions at Month 12
    End point description
    The number of Gd-enhancing T1-lesions per MRI scan was measured as the total number of Gd-enhancing T1-lesions that occurred at month 12. Includes participants with non-missing MRI results and included to the analysis population.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    382
    388
    397
    Units: Lesions
        least squares mean (confidence interval 95%)
    0.433 (0.295 to 0.635)
    0.160 (0.106 to 0.242)
    0.287 (0.197 to 0.418)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.256
         upper limit
    		 0.536
    Notes
    [9] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.05 level.
    [10] - Adjusted for region, age at baseline, and the baseline number of GdE lesions. The natural log transformation of number of available MRI scans at 12 month (1 scan per subject) is used as an offset term.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    779
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.0182 [12]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.662
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.471
         upper limit
    		 0.932
    Notes
    [11] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.05 level.
    [12] - Adjusted for region, age at baseline, and the baseline number of GdE lesions. The natural log transformation of number of available MRI scans at 12 month (1 scan per subject) is used as an offset term.

    Secondary: Time to 3-month Confirmed Disability Worsening on Expanded Disability Status Scale (EDSS)

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    End point title
    		 Time to 3-month Confirmed Disability Worsening on Expanded Disability Status Scale (EDSS)
    End point description
    The Expanded Disability Status Scale (EDSS) is an ordinal scale instrument widely accepted to evaluate disability status at a particular time and disability progression over time in patients and MS clinical studies. The disability level is based on a neurological examination to obtain scores in seven neurologic functional systems (FSs) and an ambulation score that are combined to determine the overall EDSS score (step) ranging from 0 (normal) to 10 (death due to MS). The FSs are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and Cerebral. Ambulation is measured based on if restriction is present and assisted required as well as minimum distance level achieved.
    End point type
    Secondary
    End point timeframe
    Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period.
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    448 [13]
    447 [14]
    451 [15]
    Units: days
    median (confidence interval 95%)
        3 months|
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [13] - Not estimable as there were insufficient disability events at 3 months
    [14] - Not estimable as there were insufficient disability events at 3 months
    [15] - Not estimable as there were insufficient disability events at 3 months
    Statistical analysis title
    		 Analysis of confirmation after 3 months
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3055 [16]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.402
    Notes
    [16] - Based on the Cox proportional hazard model with factors for treatment group, adjusted for region, age at baseline, and baseline EDSS score.
    Statistical analysis title
    		 Analysis of confirmation after 3 months
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7163 [17]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.886
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.705
    Notes
    [17] - Based on the Cox proportional hazard model with factors for treatment group, adjusted for region, age at Baseline, and Baseline EDSS score.

    Secondary: Percentage of Patients who Were Gadolinium Enhancing (GdE) Lesion-Free at Month 12

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    End point title
    		 Percentage of Patients who Were Gadolinium Enhancing (GdE) Lesion-Free at Month 12
    End point description
    Participants were considered lesion free at Month 12 if they did not show evidence of GdE lesions from the date of the first study treatment to their month 12 MRI Scan. The ITT population consisted of all randomized participants who received at least 1 dose of study medication. Non-responder imputation was used.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    448
    447
    451
    Units: percentage of participants
        number (confidence interval 95%)
    74.1 (69.7 to 78.5)
    85.3 (81.8 to 88.8)
    77.6 (73.5 to 81.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    11.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.59
         upper limit
    		 16.86
    Notes
    [18] - Based on the Cochran-Mantel-Haenszel test stratified by region and Expanded Disability Status Scale category per Interactive Voice Response System (IVRS).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.281 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.51
         upper limit
    		 9.51
    Notes
    [19] - Based on the Cochran-Mantel-Haenszel test stratified by region and Expanded Disability Status Scale category per Interactive Voice Response System.

    Secondary: Percentage of Patients Who Were T2 Lesion-Free at Month 12

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    End point title
    		 Percentage of Patients Who Were T2 Lesion-Free at Month 12
    End point description
    Participants were considered T2 lesion free at Month 12 if they did not show evidence of a relapse in T2 lesions from the date of the first study treatment to study completion at month 12. The ITT population consisted of all randomized participants who received at least 1 dose of study medication; analysis included non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    448
    447
    451
    Units: percentage of participants
        number (confidence interval 95%)
    27.5 (23.0 to 32.0)
    32.2 (27.6 to 36.9)
    30.0 (25.5 to 34.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1523 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    4.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 11.18
    Notes
    [20] - Based on the Cochran-Mantel-Haenszel test stratified by region and Expanded Disability Status Scale category per IVRS.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4628 [21]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    2.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.86
         upper limit
    		 8.84
    Notes
    [21] - Based on the Cochran-Mantel-Haenszel test stratified by region and Expanded Disability Status Scale category per IVRS.

    Secondary: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 12

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    End point title
    		 Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 12
    End point description
    Brain volumes were reported in cm^3. If the data were collected in mm3, then a transformation was applied by dividing the result in mm3 by 1000 to convert to cm3 prior to analysis. Atrophy was measured by MRI scan. Actual brain volumes, change from baseline to each visit, and percent change from baseline to each visit was measured. The ITT population consisted of all randomized participants who received at least 1 dose of study medication. Last Observation Carried Forward (LOCF). Imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    445
    447
    450
    Units: Percent Change
    median (full range (min-max))
        Baseline
    1445.526 (1222.70 to 1635.16)
    1458.301 (1190.84 to 1662.99)
    1453.033 (1195.40 to 1642.53)
        Change from baseline at month 12
    -0.57 (-3.7 to 1.1)
    -0.39 (-2.8 to 2.1)
    -0.50 (-2.7 to 1.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    892
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.28
    Notes
    [22] - Rank Ancova
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    892
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0615 [23]
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.2
    Notes
    [23] - Rank Ancova

    Secondary: Change from Baseline in Multiple Sclerosis Functional Composite (MSFC) Score (Including the Low-Contrast Letter Acuity Test [LCLA] to Month 12

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    End point title
    		 Change from Baseline in Multiple Sclerosis Functional Composite (MSFC) Score (Including the Low-Contrast Letter Acuity Test [LCLA] to Month 12
    End point description
    The MSFC-LCLA is a battery including the following 4 individual 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 (9HPT) is a quantitative measure of upper extremity (arm and hand) function • The Symbol Digit Modalities Test (SDMT) is a measure of executive cognitive function that assesses processing speed, flexibility, and calculation ability • Low-Contrast Letter Acuity Test (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 score. A score of +1 indicates that, on average, an individual scored 1 standard deviation (SD) better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    447
    447
    450
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.022 ± 0.334
    0.003 ± 0.328
    -0.007 ± 0.351
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    894
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.129 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    0.034
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.077
    Notes
    [24] - Adjusted for region, EDSS category per IVRS and the baseline MSFC score.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    897
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4942 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.028
         upper limit
    		 0.059
    Notes
    [25] - Adjusted for region, EDSS category per IVRS and the baseline MSFC score.

    Secondary: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 12

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    End point title
    		 Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 12
    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, including statistical analysis are reported. The single item measures are satisfaction with sexual function and change in health. Each domain has a range from 0 to 100 where higher means better.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    448
    447
    451
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical health composite summary|
    0.046 ± 12.578
    1.925 ± 11.870
    1.414 ± 12.343
        Mental health composite summary|
    -0.123 ± 15.240
    0.260 ± 15.800
    0.283 ± 15.686
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of Physical Health Composite Summary
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0364 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.642
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.104
         upper limit
    		 3.18
    Notes
    [26] - Adjusted for region, EDSS category per IVRS, and the baseline summary scores of interest.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis of Physical Health Composite Summary
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1905 [27]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 2.559
    Notes
    [27] - Adjusted for region, EDSS category per IVRS, and the baseline summary scores of interest.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.7104
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.356
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.523
         upper limit
    		 2.2234
    Notes
    [28] - Analysis of Mental Health Composite
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.8587 [30]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.045
         upper limit
    		 1.705
    Notes
    [29] - Analysis of Mental Health Composite
    [30] - Adjusted for region, EDSS category per IVRS, and the baseline summary scores of interest.

    Secondary: Number of Subjects with Treatment Emergent Adverse Events

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    End point title
    		 Number of Subjects with Treatment Emergent Adverse Events
    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 treatment-emergent adverse event (TEAE) = an AE with a start date on or after the date of first dose of IP, up through the lst dose of IP in the open-label extension Study RPC01-3001 for those who continued into the open-label extension. 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.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study medication to 28 days following the final dose of study medication; the mean duration of exposure to study drug was 410.3 days for IFN, 412.7 days for Ozanimod 0.5 mg and 414.1 days for Ozanimod 1 mg
    End point values
    		 IFN β-1a Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    445
    448
    453
    Units: participants
        Any TEAE
    336
    268
    259
        Any Moderate or Severe TEAE
    182
    138
    113
        Any Severe TEAE
    10
    7
    10
        Any Suspected TEAE
    83
    91
    76
        Any Related TEAE
    13
    7
    8
        Any Serious TEAE
    11
    13
    16
        Any Suspected Serious TEAE
    0
    3
    0
        Any Related Serious TEAE
    0
    1
    0
        Any TEAE Leading to Stopping of Study Drug
    16
    13
    7
        Any TEAE Leading to Study Withdrawal
    16
    13
    7
        Any Death
    0
    0
    0
        Any Death related to Study Drug
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Time to 6-month Confirmed Disability Worsening on Expanded Disability Status Scale (EDSS)

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    End point title
    		 Time to 6-month Confirmed Disability Worsening on Expanded Disability Status Scale (EDSS)
    End point description
    The Expanded Disability Status Scale (EDSS) is an ordinal scale instrument widely accepted to evaluate disability status at a particular time and disability progression over time in patients and MS clinical studies. The disability level is based on a neurological examination to obtain scores in seven neurologic functional systems (FSs) and an ambulation score that are combined to determine the overall EDSS score (step) ranging from 0 (normal) to 10 (death due to MS). The FSs are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and Cerebral. Ambulation is measured based on if restriction is present and assisted required as well as minimum distance level achieved.
    End point type
    Secondary
    End point timeframe
    Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period.
    End point values
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Number of subjects analysed
    448 [31]
    447 [32]
    451 [33]
    Units: days
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [31] - Not estimable as there were insufficient disability events at 3 months
    [32] - Not estimable as there were insufficient disability events at 3 months
    [33] - Not estimable as there were insufficient disability events at 3 months
    Statistical analysis title
    		 Analysis of confirmation after 6 months
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 1 mg
    Number of subjects included in analysis
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6725 [34]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.238
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 3.337
    Notes
    [34] - Based on the Cox proportional hazard model with factors for treatment group, adjusted for region, age at baseline and baseline EDSS score
    Statistical analysis title
    		 Analysis of confirmation after 6 months
    Comparison groups
    Interferon Beta-1a (IFN β-1a) v Ozanimod 0.5 mg
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3755 [35]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.535
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.595
         upper limit
    		 3.963
    Notes
    [35] - Based on the Cox proportional hazard model with factors for treatment group, adjusted for region, age at baseline and baseline EDSS score

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study medication treatment until 28 days following the last dose of treatment with the study drug.
    Adverse event reporting additional description
    The mean exposure to study drug was 410.3 days for IFN, 412.7 days for Ozanimod 0.5 mg and 414.1 days for Ozanimod 1 mg
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Interferon Beta-1a (IFN β-1a)
    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 every day for one year.

    Reporting group title
    Ozanimod 1 mg
    Reporting group description
    		 Participants received Ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for one year.

    Reporting group title
    Ozanimod 0.5 mg
    Reporting group description
    		 Participants received Ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for one year.

    Serious adverse events
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 445 (2.47%)
    13 / 448 (2.90%)
    16 / 453 (3.53%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Ovarian Tumour
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma Of Breast
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Breast Carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular Seminoma (Pure) Stage I
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menometrorrhagia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal Haemorrhage
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Fibrin D Dimer Increased
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye Injury
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical Radiculopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular Encephalopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Ulcer
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder Polyp
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendiceal Abscess
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 448 (0.00%)
    1 / 453 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lyme Disease
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 448 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative Abscess
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 448 (0.22%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Interferon Beta-1a (IFN β-1a) Ozanimod 1 mg Ozanimod 0.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    273 / 445 (61.35%)
    57 / 448 (12.72%)
    88 / 453 (19.43%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 445 (5.62%)
    34 / 448 (7.59%)
    27 / 453 (5.96%)
         occurrences all number
    39
    46
    47
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    227 / 445 (51.01%)
    17 / 448 (3.79%)
    18 / 453 (3.97%)
         occurrences all number
    706
    23
    20
    Pyrexia
         subjects affected / exposed
    28 / 445 (6.29%)
    5 / 448 (1.12%)
    5 / 453 (1.10%)
         occurrences all number
    299
    6
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 445 (8.09%)
    30 / 448 (6.70%)
    44 / 453 (9.71%)
         occurrences all number
    50
    47
    64
    Upper Respiratory Tract Infection
         subjects affected / exposed
    24 / 445 (5.39%)
    18 / 448 (4.02%)
    31 / 453 (6.84%)
         occurrences all number
    29
    21
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2014
    The following changes were made in response to US Food and Drug Administration (FDA) correspondence dated 28 February 2013 and agreed upon under a Special Protocol Assessment (SPA): The duration of the study was increased to provide additional data for assessment of accumulation of disability and the investigational plan, study schedule, objectives, endpoints, and statistical plans were updated accordingly; Planned statistical analyses text was updated; An MRI assessment at 6 months was added, text was updated to clarify that disability progression cannot be evaluated during a relapse, exclusion criteria was updated to allow enrollment of more subjects with diabetes mellitus, PK sampling schedule was clarified. • Minor changes to procedures, excluded medications, screening criteria/procedures Changes previously made for RPC01-201 Protocol Amendment 2 dated 09 August 2013 (Serial No. 0024) and agreed to on 03 December 2013 • Administrative changes - minor clarifications, corrections of inconsistencies between sections of the protocol, and correction of typographical errors
    27 Jul 2015
    • The sponsor’s address was updated • The Schedule of Assessments was modified to clarify the End of Treatment visit procedures • A maximum dose was added for citalopram in the table of prohibited cardiac medications • The Expanded Disability Status Scale functional system categories were corrected • Clarified that the use of an automated BP device is not required • Minor editorial and typographical corrections

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

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