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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
    		 2010-020337-99
    Trial protocol
    		 GB   FR   CZ   LV   HU   FI   DE   BE   SK   AT   NL   LT   EE   PT   BG   ES   PL   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    03 Jun 2016
    First version publication date
    03 Jun 2016
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WA21092
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01247324
    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
    02 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Apr 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
    31 Aug 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: 8
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Peru: 22
    Country: Number of subjects enrolled
    Russian Federation: 67
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Tunisia: 8
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    United States: 210
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 69
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Czech Republic: 130
    Country: Number of subjects enrolled
    Estonia: 16
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Lithuania: 17
    Worldwide total number of subjects
    821
    EEA total number of subjects
    409
    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)
    821
    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 1051 subjects were screened for entry into the study. 821 subjects were entered into the double-blind treatment period. Subjects who completed the 96-week double-blind treatment had an option to enter a single group, active treatment open label extension, providing they fulfilled the eligibility criteria.

    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 microgram (mcg) subcutaneous (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 subsequent 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 milligram (mg) IV as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent doses 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
    411
    410
    Completed
    340
    366
    Not completed
    71
    44
         Consent withdrawn by subject
    13
    8
         Physician decision
    -
    1
         Adverse Event
    25
    13
         Death
    1
    -
         Pregnancy
    2
    3
         Non-compliance with study drug
    3
    -
         Non-compliance
    2
    -
         Protocol Violation
    1
    2
         Unspecified
    11
    8
         Lost to follow-up
    1
    1
         Lack of efficacy
    12
    8

    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
    		 411 410 821
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.9 ( 9.3 ) 37.1 ( 9.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 272 270 542
        Male
    		 139 140 279

    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
    411
    410
    Units: relapses
        number (confidence interval 95%)
    0.292 (0.235 to 0.361)
    0.156 (0.122 to 0.2)
    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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative Binomial Model
    Parameter type
    		 Ratio (Ocrelizumab / Interferon beta-1a)
    Point estimate
    0.536
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.719

    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
    411
    410
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    		 Time to onset 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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0139
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.9
    Statistical analysis title
    		 Time to onset 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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0278
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.95

    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
    411
    410
    Units: lesions
        number (not applicable)
    337
    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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative Binomial Model
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.032
         upper limit
    		 0.104

    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
    411
    410
    Units: lesions
        number (not applicable)
    1916
    430
    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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative Binomial Model
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.174
         upper limit
    		 0.3

    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
    306 [1]
    310
    Units: percentage of subjects
        number (confidence interval 95%)
    12.42 (8.94 to 16.64)
    20 (15.69 to 24.89)
    Notes
    [1] - Number of subjects who were evaluable for this endpoint.
    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 was constructed using Pearson-Clopper method.
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0106
    Method
    		 CMH Chi-Squared test (stratified)
    Parameter type
    		 Relative risk (stratified)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 2.33

    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
    411
    410
    Units: lesions
        number (not applicable)
    1307
    564
    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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Adjusted rate ratio
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.428
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.328
         upper limit
    		 0.557

    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 + Zcognitive} /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
    411
    410
    Units: units on a scale
    arithmetic mean (standard error)
        Unadjusted Baseline mean (n= 359, 360)
    0.028 ( 0.034 )
    -0.012 ( 0.04 )
        Adjusted Week 96 mean (n= 308, 322)
    0.174 ( 0.031 )
    0.213 ( 0.031 )
    Statistical analysis title
    		 MSFC score baseline to 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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3261
    Method
    		 mixed-effect model of repeated measures
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.039
         upper limit
    		 0.116
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039

    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 “normalized” 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
    267
    281
    Units: percent change
        arithmetic mean (standard error)
    -0.741 ( 0.046 )
    -0.572 ( 0.044 )
    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
    548
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0042
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.168
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.053
         upper limit
    		 0.283
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058

    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 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
    411
    410
    Units: units on a scale
    arithmetic mean (standard error)
        Unadjusted Baseline mean (n= 338, 357)
    45.399 ( 0.529 )
    45.065 ( 0.507 )
        Adjusted mean change at week 96(n= 276, 315)
    -0.657 ( 0.475 )
    0.036 ( 0.456 )
    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
    821
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2193
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.693
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.414
         upper limit
    		 1.8
    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 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
    291 [2]
    289 [3]
    Units: percentage of subjects
        number (confidence interval 95%)
    27.1 (22.1 to 32.6)
    47.4 (41.5 to 53.3)
    Notes
    [2] - Number of subjects who were evaluable for this endpoint.
    [3] - Number of subjects who were evaluable for this endpoint.
    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 was constructed using Pearson-Clopper method
    Comparison groups
    Interferon beta-1a 44 mcg SC v Ocrelizumab
    Number of subjects included in analysis
    580
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 CMH Chi-Squared test (stratified)
    Parameter type
    		 Relative risk (stratified)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.39
         upper limit
    		 2.17

    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
    409
    408
    Units: subjects
    331
    327
    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) [4]
    End point description
    The pharmacokinetics 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
    [4] - 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
    393
    Units: microgram per milliltre*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
    409
    408
    Units: subjects
        Positive sample at baseline (n= 397, 396)
    2
    1
        Positive for ADA post-baseline (n= 401, 402)
    2
    1
    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
    32 / 409 (7.82%)
    28 / 408 (6.86%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland adenoma
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hyperventilation
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus congestion
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    3 / 409 (0.73%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 409 (0.24%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site cellulitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic arthritis staphylococcal
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (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 / 409 (0.24%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    257 / 409 (62.84%)
    241 / 408 (59.07%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    30 / 409 (7.33%)
    125 / 408 (30.64%)
         occurrences all number
    46
    234
    Nervous system disorders
    Headache
         subjects affected / exposed
    54 / 409 (13.20%)
    33 / 408 (8.09%)
         occurrences all number
    64
    51
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    85 / 409 (20.78%)
    15 / 408 (3.68%)
         occurrences all number
    97
    15
    Injection site erythema
         subjects affected / exposed
    74 / 409 (18.09%)
    0 / 408 (0.00%)
         occurrences all number
    76
    0
    Fatigue
         subjects affected / exposed
    28 / 409 (6.85%)
    21 / 408 (5.15%)
         occurrences all number
    33
    22
    Psychiatric disorders
    Depression
         subjects affected / exposed
    24 / 409 (5.87%)
    28 / 408 (6.86%)
         occurrences all number
    24
    32
    Insomnia
         subjects affected / exposed
    15 / 409 (3.67%)
    21 / 408 (5.15%)
         occurrences all number
    17
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    28 / 409 (6.85%)
    25 / 408 (6.13%)
         occurrences all number
    29
    26
    Back pain
         subjects affected / exposed
    20 / 409 (4.89%)
    25 / 408 (6.13%)
         occurrences all number
    25
    28
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    56 / 409 (13.69%)
    52 / 408 (12.75%)
         occurrences all number
    81
    93
    Upper respiratory tract infection
         subjects affected / exposed
    35 / 409 (8.56%)
    59 / 408 (14.46%)
         occurrences all number
    44
    83
    Nasopharyngitis
         subjects affected / exposed
    43 / 409 (10.51%)
    43 / 408 (10.54%)
         occurrences all number
    55
    61
    Sinusitis
         subjects affected / exposed
    25 / 409 (6.11%)
    19 / 408 (4.66%)
         occurrences all number
    27
    23

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2011
    1. The study design has been changed from rater blind to double blind, double dummy design to improve the robustness of the study. 2. The 400 mg dose of ocrelizumab has been removed leaving a single dose of ocrelizumab 600 mg; as a consequence the total number of subjects has decreased from 1200 to 800 (due to the removal of the 400 mg dose arm). The 600 mg dose of ocrelizumab has been established as the lowest, maximally effective dose, based on the results from phase II study in RRMS (WA21493/ACT4422g).
    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.
    14 Mar 2013
    1. Inclusion of an OLE phase under the same protocol.
    04 Sep 2014
    1. 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.

    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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