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    Clinical Trial Results:
    A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate The Efficacy And Safety Of Ocrelizumab In Comparison To Interferon Beta-1a (Rebif®) In Patients With Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    2010-020315-36
    Trial protocol
    SK   BE   SE   DE   ES   GB   BG   FR   IE   IT   CZ  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jun 2016
    First version publication date
    03 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA21093
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01412333
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    12 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of ocrelizumab compared with interferon beta-1a 44 mcg subcutaneous (SC) in patients with relapsing multiple sclerosis (RMS).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    11 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 9
    Country: Number of subjects enrolled
    Belarus: 15
    Country: Number of subjects enrolled
    Brazil: 10
    Country: Number of subjects enrolled
    Canada: 84
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    Mexico: 31
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    United States: 226
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 139
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 34
    Worldwide total number of subjects
    835
    EEA total number of subjects
    369
    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)
    835
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1045 subjects were screened for entry into the study. Of these, 210 subjects failed screening; the main reasons were failure to meet the inclusion/exclusion criteria or unacceptable laboratory values. A total of 835 subjects were enrolled into the study.

    Period 1
    Period 1 title
    Double Blind Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Treatment was administered in a double-blind, double-dummy fashion in order to maintain blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Interferon beta-1a 44 mcg SC
    Arm description
    Subjects with relapsing multiple sclerosis (RMS) who experienced at least either two documented clinical relapses within 2 years or one clinical relapse within 1 year prior to screening received interferon beta-1a three times per week (with placebo infusions matching ocrelizumab every 24 weeks).
    Arm type
    Active comparator

    Investigational medicinal product name
    Interferon beta-1a
    Investigational medicinal product code
    Other name
    Rebif
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received placebo infusions matching ocrelizumab infusions of 300 mg on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsquent doses every 24 weeks.

    Arm title
    Ocrelizumab
    Arm description
    Subjects with RMS who experienced at least either two documented clinical relapses within 2 years or one clinical relapse within 1 year prior to screening received ocrelizumab every 24 weeks (with placebo injections matching interferon beta-1a SC three times per week).
    Arm type
    Experimental

    Investigational medicinal product name
    Ocrelizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsquent infusions every 24 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo injections matching interferon beta-1a SC three times per week.

    Number of subjects in period 1
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Started
    418
    417
    Completed
    320
    360
    Not completed
    98
    57
         Death
    1
    1
         Physician decision
    -
    1
         Other
    16
    10
         Non-compliance with study drug
    1
    1
         Protocol violation
    1
    1
         Non-compliance
    1
    3
         Lack of efficacy
    15
    6
         Pregnancy
    3
    -
         Consent withdrawn by subject
    25
    12
         Adverse Event
    25
    16
         Lost to follow-up
    10
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Interferon beta-1a 44 mcg SC
    Reporting group description
    Subjects with relapsing multiple sclerosis (RMS) who experienced at least either two documented clinical relapses within 2 years or one clinical relapse within 1 year prior to screening received interferon beta-1a three times per week (with placebo infusions matching ocrelizumab every 24 weeks).

    Reporting group title
    Ocrelizumab
    Reporting group description
    Subjects with RMS who experienced at least either two documented clinical relapses within 2 years or one clinical relapse within 1 year prior to screening received ocrelizumab every 24 weeks (with placebo injections matching interferon beta-1a SC three times per week).

    Reporting group values
    Interferon beta-1a 44 mcg SC Ocrelizumab Total
    Number of subjects
    418 417 835
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.4 ± 9 37.2 ± 9.1 -
    Gender categorical
    Units: Subjects
        Female
    280 271 551
        Male
    138 146 284

    End points

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    End points reporting groups
    Reporting group title
    Interferon beta-1a 44 mcg SC
    Reporting group description
    Subjects with relapsing multiple sclerosis (RMS) who experienced at least either two documented clinical relapses within 2 years or one clinical relapse within 1 year prior to screening received interferon beta-1a three times per week (with placebo infusions matching ocrelizumab every 24 weeks).

    Reporting group title
    Ocrelizumab
    Reporting group description
    Subjects with RMS who experienced at least either two documented clinical relapses within 2 years or one clinical relapse within 1 year prior to screening received ocrelizumab every 24 weeks (with placebo injections matching interferon beta-1a SC three times per week).

    Primary: Annualised Relapse Rate (ARR) in Subjects With Relapsing Multiple Sclerosis (MS) at 96 Weeks

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    End point title
    Annualised Relapse Rate (ARR) in Subjects With Relapsing Multiple Sclerosis (MS) at 96 Weeks
    End point description
    ARR was calculated as the total number of relapses for all subjects in the treatment group divided by the total subject-years of exposure to that treatment. Intent-to-treat (ITT) population included all randomised subjects in the study.
    End point type
    Primary
    End point timeframe
    Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: relapses
        number (confidence interval 95%)
    0.29 (0.234 to 0.361)
    0.155 (0.121 to 0.198)
    Statistical analysis title
    ARR by Week 96
    Statistical analysis description
    Adjusted by Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Ratio
    Point estimate
    0.532
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.397
         upper limit
    0.714

    Secondary: Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 and 24 Weeks During the Double Blind Treatment Period

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    End point title
    Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 and 24 Weeks During the Double Blind Treatment Period
    End point description
    Disability progression was defined as an increase in the EDSS score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 This endpoint was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks or 24 weeks after the initial documentation of neurological worsening. ITT population included all randomised subjects in the study. Here, 99999 indicates median and -99999 and 99999 minimum and maximum of full range as less than 50% of subjects experience onset of CDP.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    Time to onset of CDP at week 12
    Statistical analysis description
    Hazard ratios (HR) were estimated by stratified Cox regression. Stratification factors were Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0169
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    0.92
    Statistical analysis title
    Time to onset of CDP at week 24
    Statistical analysis description
    Hazard ratios (HR) were estimated by stratified Cox regression. Stratification factors were Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.037
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.98

    Secondary: Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment

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    End point title
    Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
    End point description
    The total number of T1 gadolinium-enhancing lesions for all subjects in the treatment group divided by the total number of brain MRI scans. The total number of lesions is calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96. ITT population included all randomised subjects in the study.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: lesions
        number (not applicable)
    465
    21
    Statistical analysis title
    T1-Gd lesions
    Statistical analysis description
    Adjusted by baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. ROW).
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.029
         upper limit
    0.089

    Secondary: Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment

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    End point title
    Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
    End point description
    The total number of new and/or enlarging T2 lesions for all subjects in the treatment group divided by the total number of brain MRI scans. The total number of lesions is calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96. ITT population included all randomised subjects in the study.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: lesions
        number (not applicable)
    2103
    380
    Statistical analysis title
    Enlarging T2 hyperintense lesions
    Statistical analysis description
    Adjusted by baseline T2 lesion count, baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. ROW).
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.171
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.13
         upper limit
    0.225

    Secondary: Percentage of Subjects With Confirmed Disability Improvement (CDI) for at Least 12 Weeks

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    End point title
    Percentage of Subjects With Confirmed Disability Improvement (CDI) for at Least 12 Weeks
    End point description
    Disability improvement was assessed only for the subgroup of subjects with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. This endpoint was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. ITT population included all randomised subjects in the study. Here, number of subjects analysed signifies number of subjects who were evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    308
    318
    Units: percentage of subjects
        number (confidence interval 95%)
    18.83 (14.62 to 23.65)
    21.38 (17.01 to 26.3)
    Statistical analysis title
    Confirmed Disability Improvement for 12 weeks
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) Chi-Squared test was used. Stratified by Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0) 95 percent (%) confidence interval (CI) of proportion were constructed using Pearson-Clopper method.
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4019
    Method
    CMH Chi-Squared test (stratified)
    Parameter type
    Relative risk (stratified)
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.56

    Secondary: Number of T1 Hypointense Lesions During the Double Blind Treatment

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    End point title
    Number of T1 Hypointense Lesions During the Double Blind Treatment
    End point description
    The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) for all subjects in the treatment group divided by the total number of brain MRI scans. The total number of lesions is calculated as the sum of the individual number of new lesions at Weeks 24, 48, and 96. ITT population included all randomised subjects in the study.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: lesions
        number (not applicable)
    1484
    567
    Statistical analysis title
    T1 Hypointense Lesions
    Statistical analysis description
    Adjusted by baseline T1-hypointense lesion count, baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. ROW).
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.357
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.272
         upper limit
    0.47

    Secondary: Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96

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    End point title
    Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96
    End point description
    MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-HPT); and C) Paced Auditory Serial Addition Test (PASAT-3 version). The MSFCS is based on the concept that scores for these three dimensions⎯ (arm, leg, and cognitive function) are combined to create a single score (the MSFC) that can be used to detect change over time in a group of subjects with MS. Since the three primary measures differ in what they actually measure, a common composite score for the three different measures i.e., Z-score was selected for the purpose. MSFC Score = {Z arm, average + Z leg, average + Z cognitive} / 3.0. The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each subject at each time point. ITT population included all randomised subjects in the study. Here, n signifies the number of subjects evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: units on a scale
    arithmetic mean (standard error)
        Unadjusted Baseline mean (n= 342, 358)
    -0.001 ± 0.033
    0.026 ± 0.034
        Adjusted Week 96 mean (n= 269, 308)
    0.169 ± 0.029
    0.276 ± 0.028
    Statistical analysis title
    MSFC score at week 96
    Statistical analysis description
    Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Change = Baseline MSFCS Score + Geographical Region + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Baseline MSFCS Score*Week.
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    mixed-effect model of repeated measures
    Parameter type
    Difference in Adjusted Means
    Point estimate
    0.107
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.034
         upper limit
    0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037

    Secondary: Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96

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    End point title
    Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96
    End point description
    Brain volume was recorded as an absolute “normalised” value at the baseline visit then recorded at subsequent visits as a percentage change relative to the absolute value at the baseline visit. Therefore, brain volume at Week 24 was calculated as the brain volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from baseline visit to Week 24]/100). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week. ITT population included all randomised subjects in the study. Here, number of subjects analysed signifies number of subjects who were evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    From week 24 up to week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    259
    287
    Units: percent change
        arithmetic mean (standard error)
    -0.75 ± 0.051
    -0.638 ± 0.049
    Statistical analysis title
    Percent change in brain volume
    Statistical analysis description
    Estimates are from analysis based on MMRM using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment +Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week.
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    546
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.09
    Method
    MMRM
    Parameter type
    Difference in Adjusted Means
    Point estimate
    0.112
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.018
         upper limit
    0.241
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.066

    Secondary: Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96

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    End point title
    Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96
    End point description
    The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status. Descriptive statistics at baseline include subjects with assessment at baseline and at least one post-baseline value. ITT population. Here, n signifies the number of subjects evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    418
    417
    Units: units on a scale
    arithmetic mean (standard error)
        Unadjusted Baseline mean (n= 319, 355)
    44.552 ± 0.544
    44.307 ± 0.541
        Adjusted mean change at week 96(n=276, 315)
    -0.833 ± 0.472
    0.326 ± 0.444
    Statistical analysis title
    SF-36 PCS score at week 96
    Statistical analysis description
    Estimates are from analysis based on MMRM using unstructured covariance matrix: Change = Baseline PCS Score + Geographical Region + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Baseline PCS Score*Week.
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0404
    Method
    MMRM
    Parameter type
    Difference in Adjusted Means
    Point estimate
    1.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    2.268
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.564

    Secondary: Percentage of Subjects Who Have No Evidence of Disease Activity (NEDA) up to Week 96

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    End point title
    Percentage of Subjects Who Have No Evidence of Disease Activity (NEDA) up to Week 96
    End point description
    NEDA was defined only for subjects with a baseline EDSS score >=2.0. Subjects who completed the 96-week treatment period were considered as having evidence of disease activity if at least one protocol-defined relapse (PDR), a confirmed disability progression (CDP) event or at least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise the subject was considered as having NEDA. ITT population included all randomised subjects in the study. Here, number of subjects analysed signifies number of subjects who were evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    270
    289
    Units: percentage of subjects
        number (confidence interval 95%)
    24.1 (19.1 to 29.6)
    43.9 (38.1 to 49.9)
    Statistical analysis title
    NEDA at week 96
    Statistical analysis description
    Analysed using CMH test, stratified by Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0). 95% CI of proportion were constructed using Pearson-Clopper method.
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    CMH Chi-Squared test (stratified)
    Parameter type
    Relative risk (stratified)
    Point estimate
    1.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    2.32

    Secondary: Number of Subjects With Adverse Events (AEs)

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    End point title
    Number of Subjects With Adverse Events (AEs)
    End point description
    AEs included infusion related reactions (IRRs) and serious MS relapses, but excluded non-serious MS relapses. Serious Adverse Events (SAEs) included serious MS relapses and serious IRRs. The safety population included all subjects who received any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    417
    417
    Units: subjects
    357
    360
    No statistical analyses for this end point

    Secondary: Exposure to Ocrelizumab (Area Under the Concentration - Time Curve)

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    End point title
    Exposure to Ocrelizumab (Area Under the Concentration - Time Curve) [1]
    End point description
    The pharmacokinetics (PK) population included all subjects in the ocrelizumab group who had at least 1 measurable concentration value.
    End point type
    Secondary
    End point timeframe
    Week 96
    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: The data was only planned to be reported for Ocrelizumab reporting arm.
    End point values
    Ocrelizumab
    Number of subjects analysed
    389
    Units: microgram per millitre*day
        arithmetic mean (standard deviation)
    3513 ± 955
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Drug Antibodies (ADAs) to Ocrelizumab

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    End point title
    Number of Subjects With Anti-Drug Antibodies (ADAs) to Ocrelizumab
    End point description
    Number of subjects positive for anti-drug antibodies (ADAs) to ocrelizumab is the number of post- baseline evaluable subjects determined to have treatment-induced ADA or treatment-enhanced ADA during the study period. Baseline evaluable subjects with an ADA assay result from a baseline sample(s). The safety population included all subjects who received any study drug. Here, n signifies the number of subjects evaluable at the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 96
    End point values
    Interferon beta-1a 44 mcg SC Ocrelizumab
    Number of subjects analysed
    417
    417
    Units: subjects
        Positive sample at baseline (n= 407, 402)
    2
    4
        Positive for ADA post-baseline (n= 403, 405)
    5
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Week 96 (Double Blind Treatment Period)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Interferon beta-1a
    Reporting group description
    Subjects with relapsing multiple sclerosis (RMS) who experienced at least either two documented clinical attacks within 2 years or one clinical attack within 1 year prior to screening received interferon beta-1a three times per week (with placebo infusions matching ocrelizumab every 24 weeks).

    Reporting group title
    Ocrelizumab
    Reporting group description
    Subjects with RMS who experienced at least either two documented clinical attacks within 2 years or one clinical attack within 1 year prior to screening received ocrelizumab every 24 weeks (with placebo injections matching interferon beta-1a SC three times per week).

    Serious adverse events
    Interferon beta-1a Ocrelizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 417 (9.59%)
    29 / 417 (6.95%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Peripheral venous disease
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid Adenoma
         subjects affected / exposed
    0 / 417 (0.00%)
    2 / 417 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression Suicidal
         subjects affected / exposed
    2 / 417 (0.48%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apathy
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stress
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Dysmenorrhea
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 417 (0.24%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Spontaneous haematoma
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 417 (0.48%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 417 (0.24%)
    2 / 417 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Discomfort
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viith Nerve Paralysis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 417 (0.24%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 417 (0.48%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral Osteophyte
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 417 (0.24%)
    3 / 417 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 417 (0.48%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 417 (0.00%)
    2 / 417 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 417 (0.00%)
    1 / 417 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site cellulitis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Pericarditis
         subjects affected / exposed
    1 / 417 (0.24%)
    0 / 417 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Interferon beta-1a Ocrelizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    289 / 417 (69.30%)
    309 / 417 (74.10%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    49 / 417 (11.75%)
    157 / 417 (37.65%)
         occurrences all number
    63
    270
    Nervous system disorders
    Headache
         subjects affected / exposed
    70 / 417 (16.79%)
    60 / 417 (14.39%)
         occurrences all number
    109
    87
    Dizziness
         subjects affected / exposed
    23 / 417 (5.52%)
    16 / 417 (3.84%)
         occurrences all number
    27
    18
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    92 / 417 (22.06%)
    23 / 417 (5.52%)
         occurrences all number
    106
    25
    Fatigue
         subjects affected / exposed
    36 / 417 (8.63%)
    43 / 417 (10.31%)
         occurrences all number
    47
    56
    Injection site erythema
         subjects affected / exposed
    53 / 417 (12.71%)
    1 / 417 (0.24%)
         occurrences all number
    56
    1
    Pyrexia
         subjects affected / exposed
    24 / 417 (5.76%)
    15 / 417 (3.60%)
         occurrences all number
    33
    18
    Injection site reaction
         subjects affected / exposed
    28 / 417 (6.71%)
    2 / 417 (0.48%)
         occurrences all number
    28
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    30 / 417 (7.19%)
    34 / 417 (8.15%)
         occurrences all number
    35
    37
    Insomnia
         subjects affected / exposed
    23 / 417 (5.52%)
    25 / 417 (6.00%)
         occurrences all number
    24
    30
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 417 (4.08%)
    28 / 417 (6.71%)
         occurrences all number
    18
    31
    Arthralgia
         subjects affected / exposed
    23 / 417 (5.52%)
    21 / 417 (5.04%)
         occurrences all number
    26
    24
    Myalgia
         subjects affected / exposed
    27 / 417 (6.47%)
    12 / 417 (2.88%)
         occurrences all number
    29
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    41 / 417 (9.83%)
    79 / 417 (18.94%)
         occurrences all number
    61
    127
    Upper respiratory tract infection
         subjects affected / exposed
    52 / 417 (12.47%)
    65 / 417 (15.59%)
         occurrences all number
    87
    108
    Urinary tract infection
         subjects affected / exposed
    43 / 417 (10.31%)
    44 / 417 (10.55%)
         occurrences all number
    52
    75
    Sinusitis
         subjects affected / exposed
    20 / 417 (4.80%)
    27 / 417 (6.47%)
         occurrences all number
    25
    35
    Influenza
         subjects affected / exposed
    20 / 417 (4.80%)
    24 / 417 (5.76%)
         occurrences all number
    25
    30
    Bronchitis
         subjects affected / exposed
    13 / 417 (3.12%)
    22 / 417 (5.28%)
         occurrences all number
    15
    28

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2012
    1. Dosing preparation and infusion guidance were revised to simplify the preparation of infusion bags and dosing procedures. 2. Specific eligibility cut-off values for immunoglobulin M (IgM) and immunoglobulin G (IgG) and the re-treatment criteria for IgG were modified to reflect the central lab reference ranges. 3. Sites were informed of additional, optional sub-studies conducted at select centers in which subjects could be eligible to participate
    28 Mar 2013
    1. Inclusion of an OLE phase under the same protocol. 2. Addition of the following exploratory objectives: proportion of disease activity free subjects, defined as absence of both relapses and sustained accumulation of disability, and absence of MRI activity by Week 96; evaluation of long term safety and efficacy of ocrelizumab in the OLE study phase. 3. Clarification on how sustained disability progression was calculated
    04 Sep 2014
    1. An update to the Statistical Considerations and Analytical Plan section of the protocol in line with the SAP amendment to implement European Medicines Agency (EMA) Scientific Advice and to increase statistical rigor. 2. Conversion of the optional investigator-sponsored Roche-supported exploratory substudies to Roche-sponsored studies as per current policy of the sponsor 3. Revision of the pre-specified mandatory biomarker

    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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