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    Clinical Trial Results:
    A randomized, double-blind, parallel group, international study to evaluate the safety and efficacy of ocrelizumab compared to placebo in patients with active rheumatoid arthritis continuing methotrexate treatment

    Summary
    EudraCT number
    2006-005147-28
    Trial protocol
    DE   BE   ES   FR   AT   GR   GB  
    Global end of trial date
    22 Apr 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    06 Jan 2018
    First version publication date
    04 Aug 2017
    Other versions
    v1
    Version creation reason
    Summary report(s)
    WA20494_CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    WA20494
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00406419
    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
    Final
    Date of interim/final analysis
    22 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and safety of ocrelizumab versus placebo in reducing the signs and symptoms of rheumatoid arthritis (RA), when used in combination with methotrexate (MTX) in subjects with active RA who have an inadequate response to MTX therapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    Every patient had to take methotrexate.
    Evidence for comparator
    Comparator was placebo.
    Actual start date of recruitment
    30 Nov 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 44
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 95
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    China: 22
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Guatemala: 8
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Mexico: 79
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Panama: 9
    Country: Number of subjects enrolled
    Peru: 32
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Russian Federation: 103
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    Thailand: 25
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    United States: 360
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    1015
    EEA total number of subjects
    95
    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)
    878
    From 65 to 84 years
    135
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1015 subjects were enrolled in the study. The study consisted of 3 parts: double-blind treatment period (Day 1 - Week 48); study extension period (during which eligible subjects could receive open-label treatment with ocrelizumab, at the discretion of the investigator); safety follow-up period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo × 2 IV + MTX
    Arm description
    Subjects received two intravenous (IV) infusion matching placebo to ocrelizumab on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 milligram (mg) was administered weekly.
    Arm type
    Placebo

    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
    Matching placebo to ocrelizumab two IV infusions on Day 1 and Day 15.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate 7.5-25 mg tablet was administered weekly.

    Arm title
    Ocrelizumab 200 mg × 2 IV + MTX
    Arm description
    Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.
    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
    Two IV infusions Ocrelizumab 200 mg on Day 1 and Day 15.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate 7.5-25 mg tablet was administered weekly.

    Arm title
    Ocrelizumab 500 mg × 2 IV + MTX
    Arm description
    Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.
    Arm type
    Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate 7.5-25mg tablet was administered weekly.

    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
    Two IV infusions Ocrelizumab 500 mg on Day 1 and Day 15.

    Number of subjects in period 1
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Started
    324
    344
    347
    Completed
    0
    0
    0
    Not completed
    324
    344
    347
         Death
    3
    1
    4
         Protocol deviation
    6
    2
    5
         Other
    260
    288
    282
         Withdrawal by Subject
    17
    24
    26
         Lack of efficacy
    12
    1
    6
         NOn-Compliance with Study Drug
    5
    6
    3
         Adverse Event
    10
    12
    16
         Lost to follow-up
    11
    10
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo × 2 IV + MTX
    Reporting group description
    Subjects received two intravenous (IV) infusion matching placebo to ocrelizumab on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 milligram (mg) was administered weekly.

    Reporting group title
    Ocrelizumab 200 mg × 2 IV + MTX
    Reporting group description
    Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

    Reporting group title
    Ocrelizumab 500 mg × 2 IV + MTX
    Reporting group description
    Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

    Reporting group values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX Total
    Number of subjects
    324 344 347 1015
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.5 ± 11.6 51.8 ± 12.0 50.8 ± 12.3 -
    Gender Categorical
    Units: Subjects
        Female
    251 284 285 820
        Male
    73 60 62 195

    End points

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    End points reporting groups
    Reporting group title
    Placebo × 2 IV + MTX
    Reporting group description
    Subjects received two intravenous (IV) infusion matching placebo to ocrelizumab on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 milligram (mg) was administered weekly.

    Reporting group title
    Ocrelizumab 200 mg × 2 IV + MTX
    Reporting group description
    Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

    Reporting group title
    Ocrelizumab 500 mg × 2 IV + MTX
    Reporting group description
    Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

    Primary: Percentage of Subjects with American College of Rheumatology (ACR) 20 Response at Week 24

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    End point title
    Percentage of Subjects with American College of Rheumatology (ACR) 20 Response at Week 24
    End point description
    ACR20 is defined as 20 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). Intent-to-treat (ITT) population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    319
    343
    343
    Units: Percentage of Subjects
        number (confidence interval 95%)
    35.7 (30.5 to 41.0)
    56.9 (51.6 to 62.1)
    54.5 (49.2 to 59.8)
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    662
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    18.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11
         upper limit
    25.9
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    662
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    21.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.1
         upper limit
    28.8

    Primary: Percentage of Subjects with ACR20 Response at Week 48

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    End point title
    Percentage of Subjects with ACR20 Response at Week 48
    End point description
    ACR20 is defined as 20 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    319
    343
    343
    Units: Percentage of Subjects
        number (confidence interval 95%)
    27.6 (22.7 to 32.5)
    58.3 (53.1 to 63.5)
    62.1 (57.0 to 67.2)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    662
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    30.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.7
         upper limit
    37.9
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    662
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    34.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.4
         upper limit
    41.5

    Primary: Percentage of Subjects With Adverse Events (AEs)

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    End point title
    Percentage of Subjects With Adverse Events (AEs) [1]
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. Pre-existing conditions which worsened during the study were also reported as AEs. The safety population included all subjects who were randomized and received any part of an infusion of study drug and provided at least one assessment of safety.
    End point type
    Primary
    End point timeframe
    Up to 8.5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was planned to be reported for this endpoint.
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Percentage of Subjects
        number (not applicable)
    79.4
    82.2
    83.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Major Clinical Response (ACR70 for ≥ 6 months) at Week 48

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    End point title
    Percentage of Subjects With a Major Clinical Response (ACR70 for ≥ 6 months) at Week 48
    End point description
    ACR70 is defined as 70 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Percentage of Subjects
        number (confidence interval 95%)
    0.9 (0.0 to 2.0)
    6.1 (3.6 to 8.7)
    7.3 (4.5 to 10.0)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.2
         upper limit
    8.1
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.1
         upper limit
    9.4

    Secondary: Percentage of Subjects Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48

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    End point title
    Percentage of Subjects Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48
    End point description
    The Disease Activity Score (DAS28) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and Erythrocyte Sedimentation Rate (ESR). DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 24 (n= 319, 343, 343)
    5.3 (2.9 to 7.8)
    7.9 (5.0 to 10.7)
    10.8 (7.5 to 14.1)
        Week 48 (n= 319, 343, 343)
    5.3 (2.9 to 7.8)
    16.0 (12.2 to 19.9)
    17.5 (13.5 to 21.5)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1472
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    6.7
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0082
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    5.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    9.9
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    10.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6
         upper limit
    15.4
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    12.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.3
         upper limit
    17

    Secondary: Change From Baseline in DAS28 at Weeks 24 and 48

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    End point title
    Change From Baseline in DAS28 at Weeks 24 and 48
    End point description
    The Disease Activity Score (DAS28) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and Erythrocyte Sedimentation Rate (ESR). DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline (n= 316, 340, 336)
    6.42 ± 1.103
    6.40 ± 1.143
    6.40 ± 1.077
        Change at Week 24 (n= 227, 299, 300)
    -1.33 ± 1.329
    -2.00 ± 1.248
    -2.02 ± 1.310
        Change at Week 48 (n= 187, 271, 278)
    -1.38 ± 1.290
    -2.42 ± 1.504
    -2.68 ± 1.475
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    -0.4
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    -0.5
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    -0.8
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    -1

    Secondary: European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48

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    End point title
    European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48
    End point description
    DAS 28 score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and ESR. DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. EULAR Good response: DAS28 ≤ 3.2 and a change from Baseline < -1.2. EULAR Moderate response: DAS28 >3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2. ITT population included all randomised subjects who had received any part of an infusion of study medication. Data for good /moderate response are grouped. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Percentage of Subjects
    number (not applicable)
        Week 24
    41.6
    68.8
    70.0
        Week 48
    35.3
    65.9
    72.0
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.09
         upper limit
    3.82
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.24
         upper limit
    4.11
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.77
         upper limit
    5.1
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.36
         upper limit
    6.23

    Secondary: Percentage of Subjects Achieving an ACR50 Response at Weeks 24 and 48

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    End point title
    Percentage of Subjects Achieving an ACR50 Response at Weeks 24 and 48
    End point description
    ACR50 is defined as 50 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 24 (n= 319, 343, 343)
    16.3 (12.2 to 20.4)
    31.8 (26.9 to 36.7)
    31.2 (26.3 to 36.1)
        Week 48 (n= 319, 343, 343)
    12.9 (9.2 to 16.5)
    39.9 (34.8 to 45.1)
    36.7 (31.6 to 41.8)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    15.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.5
         upper limit
    22.2
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.6
         upper limit
    21.4
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    27.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.1
         upper limit
    33.6
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    23.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.4
         upper limit
    29.9

    Secondary: Percentage of Subjects Achieving an ACR70 Response at Weeks 24 and 48

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    End point title
    Percentage of Subjects Achieving an ACR70 Response at Weeks 24 and 48
    End point description
    ACR70 is defined as 70 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 24 (n= 319, 343, 343)
    5.6 (3.1 to 8.2)
    14.3 (10.6 to 18.0)
    12.2 (8.8 to 15.7)
        Week 48 (n= 319, 343, 343)
    6.6 (3.9 to 9.3)
    20.7 (16.4 to 25.0)
    22.4 (18.0 to 26.9)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    8.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.2
         upper limit
    13.3
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.4
         upper limit
    11.2
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    14.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.2
         upper limit
    19.4
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    15.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.5
         upper limit
    20.9

    Secondary: Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48
    End point description
    66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Swollen joints
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 235, 311, 308)
    -38.20 ± 66.127
    -51.82 ± 80.805
    -54.76 ± 39.896
        Change at Week 48 (n= 211, 296, 299)
    -39.39 ± 59.184
    -61.36 ± 44.414
    -64.22 ± 65.234
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48
    End point description
    68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    243
    243
    Units: Tendor joints
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 235, 311, 308)
    -36.97 ± 58.675
    -55.11 ± 37.962
    -51.07 ± 49.700
        Change at Week 48 (n= 211, 296, 299)
    -35.91 ± 64.358
    -61.51 ± 37.229
    -59.55 ± 48.474
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48
    End point description
    The patient assessed their pain on a 0 to 100 millimeters (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as “no pain” and the right-hand extreme equals 100 mm as “unbearable pain”. A negative change indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 24 (n =230, 307, 304)
    -9.10 ± 109.646
    -32.02 ± 88.637
    -27.73 ± 139.732
        Change at Week 48 (n =206, 293, 295)
    -2.28 ± 148.933
    -38.86 ± 104.267
    -32.47 ± 197.692
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Physician’s Global VAS at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in Physician’s Global VAS at Weeks 24 and 48
    End point description
    The physician’s global assessment of disease activity is assessed on a 0 to 100 millimetres (mm) horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as “no disease activity” (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as “maximum disease activity” (maximum arthritis disease activity). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 234, 311, 307)
    -40.23 ± 39.655
    -51.44 ± 34.669
    -53.02 ± 34.479
        Change at Week 48 (n= 210, 296, 298)
    -41.60 ± 43.285
    -61.29 ± 31.543
    -62.10 ± 30.866
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Patient’s Global VAS at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in Patient’s Global VAS at Weeks 24 and 48
    End point description
    The patient’s global assessment of disease activity is assessed on a 0 to 100 millimeters (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and is described as “no disease activity” (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as “maximum disease activity” (maximum arthritis disease activity). A negative change from Baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 231, 308, 303)
    -20.73 ± 74.480
    -37.96 ± 83.908
    -36.99 ± 79.130
        Change at Week 48 (n= 207, 294, 294)
    -17.13 ± 100.706
    -42.02 ± 103.526
    -55.26 ± 37.873
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48
    End point description
    The serum concentration of C-Reactive Protein (CRP) is measured in milligrams per deciliter (mg/dL). A reduction in the level is considered an improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Milligrams per deciliter (mg/dL)
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 235, 311, 308)
    11.64 ± 116.697
    -30.41 ± 109.193
    -23.07 ± 109.193
        Change at Week 48 (n= 211, 296, 299)
    22.01 ± 190.346
    -40.89 ± 90.139
    15.14 ± 820.007
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48
    End point description
    HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 231, 301, 305)
    -20.11 ± 48.921
    -30.12 ± 86.217
    -40.83 ± 38.243
        Change at Week 48 (n= 207, 286, 296)
    -22.67 ± 57.893
    -35.47 ± 78.670
    -45.63 ± 39.241
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48

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    End point title
    Percent Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48
    End point description
    The Erythrocyte Sedimentation Rate (ESR) was measured in millimeters per hour (mm/hr). A reduction in the level is considered an improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Millimeters per hour (mm/hr)
    arithmetic mean (standard deviation)
        Change at Week 24 (n= 234, 311, 308)
    -2.51 ± 66.453
    -20.10 ± 90.059
    -29.98 ± 57.195
        Change at Week 48 (n= 211, 296, 299)
    -2.72 ± 90.088
    -27.24 ± 147.973
    -41.19 ± 55.485
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48

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    End point title
    Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48
    End point description
    mTSS: measure of joint damage that combines scores for bone erosion and joint space narrowing (JNS). Erosion score: total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=normal to 3.5=very severe erosion. JNS score: total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mTSS scores ranged from 0 (normal) to 292 (worst possible total score). Change= mTSS score at Week 24 minus score at baseline. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. mITT population. Number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    305
    322
    329
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 305, 322, 329)
    33.58 ± 51.106
    31.45 ± 51.323
    31.99 ± 49.602
        Change at Week 24 (n= 268, 308, 313)
    1.04 ± 2.842
    0.34 ± 2.424
    -0.03 ± 2.534
        Change at Week 48 (n= 268, 308, 313)
    1.74 ± 5.293
    0.26 ± 2.791
    -0.03 ± 2.911
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0024
    Method
    Van Elteren's test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Van Elteren's test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Van Elteren's test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Van Elteren's test
    Confidence interval

    Secondary: Change From Baseline in Modified Erosion Score at Weeks 24 and 48

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    End point title
    Change From Baseline in Modified Erosion Score at Weeks 24 and 48
    End point description
    Erosion score was defined as a total of 14 locations in each hand and wrist and 6 joints in the foot using an 8-point scale where 0=normal to 3.5=very severe erosion. mITT population included all subjects who were in the ITT analysis set and had both baseline radiograph and at least one post-baseline radiograph for campaign 1. Here, the number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    305
    322
    329
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 305, 322, 329)
    17.10 ± 27.256
    16.22 ± 27.875
    16.24 ± 26.103
        Change at Week 24 (n= 268, 308, 313)
    0.61 ± 1.778
    0.18 ± 1.487
    0.04 ± 1.511
        Change at week 48 (n= 268, 308, 313)
    1.06 ± 3.238
    0.08 ± 1.690
    -0.08 ± 1.588
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0015
    Method
    Van Elteren’s test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Van Elteren’s test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Van Elteren’s test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Van Elteren’s test
    Confidence interval

    Secondary: Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48

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    End point title
    Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48
    End point description
    Joint Space Narrowing score was defined as a total of 13 locations in each hand and wrist and 6 joints in the foot using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mITT population included all subjects who were in the ITT analysis set and had both baseline radiograph and at least one post-baseline radiograph for campaign 1. Here, the number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    305
    322
    329
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 305, 322, 329)
    16.47 ± 25.990
    15.22 ± 25.012
    15.75 ± 25.118
        Change at Week 24 (n= 268, 308, 313)
    0.43 ± 1.654
    0.16 ± 1.655
    -0.07 ± 1.504
        Change at Week 48 (n= 268, 308, 313)
    0.68 ± 2.777
    0.18 ± 1.471
    0.05 ± 1.859
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0923
    Method
    Van Elteren’s test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Van Elteren’s test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1171
    Method
    Van Elteren’s test
    Confidence interval
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Van Elteren’s test
    Confidence interval

    Secondary: Percentage of Subjects Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48

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    End point title
    Percentage of Subjects Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48
    End point description
    Radiographic progression was defined as a change from baseline in the modified total sharp scale greater than zero. The modified Intent-to-Treat (mITT) population included all subjects who were in the ITT analysis set and had both baseline radiograph and at least one post-baseline radiograph for campaign 1. Here, the number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    305
    322
    329
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 24 (n= 305, 322, 329)
    47.5 (41.9 to 53.1)
    58.7 (53.3 to 64.1)
    65.3 (60.2 to 70.5)
        Week 48 (n= 305, 322, 329)
    37.7 (32.3 to 43.1)
    58.7 (53.3 to 64.1)
    60.8 (55.5 to 66.1)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0036
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    11.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.8
         upper limit
    19.2
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    18.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.6
         upper limit
    25.8
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    21.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.7
         upper limit
    28.9
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    23.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.1
         upper limit
    31.2

    Secondary: Percentage of Subjects With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48

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    End point title
    Percentage of Subjects With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48
    End point description
    mTSS: measure of joint damage that combines scores for bone erosion and joint space narrowing (JNS). Erosion score: total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=normal to 3.5=very severe erosion. JNS score: total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mTSS scores ranged from 0 (normal) to 292 (worst possible total score). Change= mTSS score at Week 24 minus score at baseline. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. mITT population. Number of subjects analysed signifies subjects who were evaluated for the endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    305
    322
    329
    Units: Percentage of Subjects
        number (confidence interval 95%)
    11.8 (8.2 to 15.4)
    22.7 (18.1 to 27.2)
    29.8 (24.8 to 34.7)
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    18.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.1
         upper limit
    24.4
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    10.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5
         upper limit
    16.8

    Secondary: Percentage of Subjects With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and 48

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    End point title
    Percentage of Subjects With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and 48
    End point description
    HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 24 (n= 319, 343, 343)
    42.3 (36.9 to 47.7)
    59.8 (54.6 to 65.0)
    66.5 (61.5 to 71.5)
        Week 48 (n= 319, 343, 343)
    34.8 (29.6 to 40.0)
    58.9 (53.7 to 64.1)
    65.9 (60.9 to 70.9)
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    17.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10
         upper limit
    24.9
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    23.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.4
         upper limit
    31.1
    Statistical analysis title
    Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    24.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.9
         upper limit
    31.4
    Statistical analysis title
    Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    30.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.7
         upper limit
    38.1

    Secondary: Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48

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    End point title
    Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48
    End point description
    The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical and Mental Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline:MCS (n= 312, 334, 334)
    40.54 ± 12.282
    39.99 ± 11.863
    40.48 ± 12.822
        Change at Week 24:MCS (n= 229, 303, 302)
    4.38 ± 10.886
    6.11 ± 10.082
    5.80 ± 11.224
        Change at Week 48:MCS (n= 206, 290, 292)
    4.15 ± 10.326
    6.36 ± 10.212
    6.43 ± 11.795
        Baseline:PCS (n= 312, 334, 334)
    31.86 ± 7.387
    32.24 ± 7.401
    31.58 ± 8.039
        Change at Week 24:PCS (n= 229, 303, 302)
    5.29 ± 8.421
    6.73 ± 8.385
    7.71 ± 7.328
        Change at Week 48:PCS (n= 206, 290, 292)
    5.28 ± 8.373
    8.38 ± 8.347
    9.15 ± 8.389
    Statistical analysis title
    MCS: Ocrelizumab 200 mg vs Placebo Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1103
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    2.8
    Statistical analysis title
    MCS: Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2011
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    2.5
    Statistical analysis title
    MCS: Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0186
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    3.6
    Statistical analysis title
    MCS: Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0127
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    3.7
    Statistical analysis title
    PCS: Ocrelizumab 200 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0232
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    2.8
    Statistical analysis title
    PCS: Ocrelizumab 500 mg vs Placebo at Week 24
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    3.6
    Statistical analysis title
    PCS: Ocrelizumab 200 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.7
         upper limit
    4.5
    Statistical analysis title
    PCS: Ocrelizumab 500 mg vs Placebo at Week 48
    Comparison groups
    Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.2
         upper limit
    5

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48

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    End point title
    Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48
    End point description
    The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 317, 340, 340)
    27.25 ± 10.821
    26.87 ± 10.920
    26.57 ± 11.194
        Change at Week 24 (n= 235, 309, 308)
    5.14 ± 9.864
    7.18 ± 9.755
    7.07 ± 10.269
        Change at Week 48 (n= 211, 296, 298)
    5.39 ± 10.054
    8.01 ± 10.132
    8.41 ± 10.682
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48

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    End point title
    Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48
    End point description
    The modified BPI (short-form) is a short questionnaire to assess the severity of pain and the impact of pain on daily functions. The first two questions relate to average and current pain respectively and are assessed on a scale from 0 to 10, where 0 represents no pain, and 10 represents pain as bad as one can imagine. The degree to which pain has interfered with 7 different aspects is also rated on a scale from 0 to 10, where 0 represents that pain does not interfere and 10 that pain completely interferes. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, 48
    End point values
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Number of subjects analysed
    320
    343
    343
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline: average pain (n=316,340,335)
    6.39 ± 2.011
    6.28 ± 2.077
    6.42 ± 2.194
        Baseline: pain right now (n=317,340,337)
    5.57 ± 2.398
    5.75 ± 2.495
    5.82 ± 2.533
        Change at Week 24: average pain (n=234,304,298)
    -1.82 ± 2.441
    -2.45 ± 2.299
    -2.48 ± 2.424
        Change at Week 24: pain right now (n=235,303,299)
    -1.57 ± 2.775
    -2.32 ± 2.659
    -2.24 ± 2.671
        Change at Week 48: average pain (n=188,273,280)
    -1.78 ± 2.619
    -2.92 ± 2.442
    -3.06 ± 2.422
        Change at Week 48: pain right now (n=188,272,282)
    -1.53 ± 2.795
    -2.66 ± 2.676
    -2.92 ± 2.681
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 8.5 years
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo × 2 IV + MTX
    Reporting group description
    Subjects received two intravenous (IV) infusion matching placebo to ocrelizumab on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 milligram (mg) was administered weekly.

    Reporting group title
    Ocrelizumab 200 mg × 2 IV + MTX
    Reporting group description
    Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

    Reporting group title
    Ocrelizumab 500 mg × 2 IV + MTX
    Reporting group description
    Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

    Serious adverse events
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    73 / 318 (22.96%)
    61 / 343 (17.78%)
    78 / 345 (22.61%)
         number of deaths (all causes)
    5
    2
    8
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid vasculitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis necrotising
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammatory carcinoma of the breast
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myxoid liposarcoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    3 / 343 (0.87%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 343 (0.58%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 343 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin abnormal
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    3 / 318 (0.94%)
    1 / 343 (0.29%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 343 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinus disorder
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 343 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 343 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Inner ear disorder
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otosalpingitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    2 / 318 (0.63%)
    3 / 343 (0.87%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stag horn calculus
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urogenital fistula
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 343 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    4 / 318 (1.26%)
    1 / 343 (0.29%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 318 (0.94%)
    4 / 343 (1.17%)
    10 / 345 (2.90%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 4
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    Urinary tract infection
         subjects affected / exposed
    4 / 318 (1.26%)
    1 / 343 (0.29%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 318 (0.94%)
    1 / 343 (0.29%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 318 (1.26%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    3 / 318 (0.94%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute hepatitis B
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Borrelia infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis gangrenous
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 343 (0.58%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mycobacterium kansasii infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Purulent synovitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 343 (0.00%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 343 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 343 (0.29%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo × 2 IV + MTX Ocrelizumab 200 mg × 2 IV + MTX Ocrelizumab 500 mg × 2 IV + MTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    228 / 318 (71.70%)
    272 / 343 (79.30%)
    273 / 345 (79.13%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 318 (8.18%)
    42 / 343 (12.24%)
    37 / 345 (10.72%)
         occurrences all number
    28
    43
    45
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    62 / 318 (19.50%)
    89 / 343 (25.95%)
    96 / 345 (27.83%)
         occurrences all number
    136
    164
    168
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 318 (2.52%)
    13 / 343 (3.79%)
    20 / 345 (5.80%)
         occurrences all number
    8
    15
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 318 (5.35%)
    13 / 343 (3.79%)
    13 / 345 (3.77%)
         occurrences all number
    19
    14
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 318 (7.55%)
    29 / 343 (8.45%)
    32 / 345 (9.28%)
         occurrences all number
    29
    33
    38
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    17 / 318 (5.35%)
    16 / 343 (4.66%)
    14 / 345 (4.06%)
         occurrences all number
    21
    18
    15
    Psychiatric disorders
    Depression
         subjects affected / exposed
    19 / 318 (5.97%)
    18 / 343 (5.25%)
    21 / 345 (6.09%)
         occurrences all number
    19
    20
    23
    Insomnia
         subjects affected / exposed
    19 / 318 (5.97%)
    19 / 343 (5.54%)
    15 / 345 (4.35%)
         occurrences all number
    19
    19
    16
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    23 / 318 (7.23%)
    21 / 343 (6.12%)
    23 / 345 (6.67%)
         occurrences all number
    28
    22
    29
    Dyspepsia
         subjects affected / exposed
    14 / 318 (4.40%)
    17 / 343 (4.96%)
    22 / 345 (6.38%)
         occurrences all number
    15
    18
    24
    Gastritis
         subjects affected / exposed
    8 / 318 (2.52%)
    14 / 343 (4.08%)
    18 / 345 (5.22%)
         occurrences all number
    9
    16
    18
    Nausea
         subjects affected / exposed
    17 / 318 (5.35%)
    15 / 343 (4.37%)
    22 / 345 (6.38%)
         occurrences all number
    21
    17
    26
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 318 (5.03%)
    19 / 343 (5.54%)
    26 / 345 (7.54%)
         occurrences all number
    17
    20
    27
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    39 / 318 (12.26%)
    43 / 343 (12.54%)
    40 / 345 (11.59%)
         occurrences all number
    57
    59
    47
    Gastroenteritis
         subjects affected / exposed
    16 / 318 (5.03%)
    11 / 343 (3.21%)
    15 / 345 (4.35%)
         occurrences all number
    22
    12
    20
    Influenza
         subjects affected / exposed
    20 / 318 (6.29%)
    31 / 343 (9.04%)
    29 / 345 (8.41%)
         occurrences all number
    26
    37
    35
    Herpes zoster
         subjects affected / exposed
    16 / 318 (5.03%)
    14 / 343 (4.08%)
    12 / 345 (3.48%)
         occurrences all number
    17
    16
    13
    Nasopharyngitis
         subjects affected / exposed
    45 / 318 (14.15%)
    43 / 343 (12.54%)
    51 / 345 (14.78%)
         occurrences all number
    60
    56
    77
    Pharyngitis
         subjects affected / exposed
    18 / 318 (5.66%)
    9 / 343 (2.62%)
    9 / 345 (2.61%)
         occurrences all number
    22
    14
    13
    Sinusitis
         subjects affected / exposed
    18 / 318 (5.66%)
    33 / 343 (9.62%)
    28 / 345 (8.12%)
         occurrences all number
    27
    48
    35
    Upper respiratory tract infection
         subjects affected / exposed
    64 / 318 (20.13%)
    79 / 343 (23.03%)
    85 / 345 (24.64%)
         occurrences all number
    130
    130
    157
    Urinary tract infection
         subjects affected / exposed
    40 / 318 (12.58%)
    38 / 343 (11.08%)
    48 / 345 (13.91%)
         occurrences all number
    67
    49
    69

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2006
    1. Provided more information on the definition and incidence of infusion-related reactions (IRRs) as applied to previous studies with ocrelizumab (2004-002132-26 and NCT00077870) 2. Included a statement mandating the signing of informed consent forms by subjects prior to the performance of any screening procedures 3. Defined the period during which subjects who withdrew from the study should continue in safety follow-up and clarified the end of study for individual subjects 4. Included some additional text cautioning the investigator to review safety criteria, which were also added to the text, prior to the administration of subsequent infusions 5. Clarified that randomisation could occur within 24 hours or exceptionally within 72 hours prior to administration of blinded study infusion 6. In the schedule of assessments added an assessment of rheumatoid manifestations; included new safety assessment for Hepatitis B viral DNA and separated inflammatory related biomarkers and Apolipoprotein A1 and B at baseline and every 24 weeks from the blood biochemistry assessments to reduce their collection time points 7. In the schedule of assessments added an assessment of rheumatoid manifestations; included new safety assessment for Hepatitis B viral DNA and separated inflammatory related biomarkers and Apolipoprotein A1 and B at baseline and every 24 weeks from the blood biochemistry assessments to reduce their collection time points 8. Recommended that IV infusion bags containing diluted ocrelizumab solutions be used within 48 hours of preparation for stability reasons 9. Provided guidance on the administration of rescue medication during the study 10. Included detailed information on the Hepatitis B screening process for inclusion into the study including information on viral DNA monitoring and separated the screening process from that for Hepatitis C
    28 Aug 2008
    1. Reduced the number of samples collected during the double-blind and study extension periods and amended the scheduled of assessments and procedures accordingly 2. Clarified the basis for the administration of Day 15 infusions for patients who develop infections between Day 1 and Day 15 of a course of study treatment 3. Clarified the circumstances under which pregnant patients and subjects who develop skin malignancy during the study could be given study treatment
    12 Jul 2010
    Terminates treatment and mandates transitioning of all subjects to safety follow up
    06 Sep 2012
    Terminates the Safety Follow up for all subjects

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/21905001
    http://www.ncbi.nlm.nih.gov/pubmed/24498318
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