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    Clinical Trial Results:
    A Phase III, multicenter, randomized, parallel-group, double blinded, placebo controlled study to evaluate the efficacy and safety of ocrelizumab in adults with Primary Progressive Multiple Sclerosis

    Summary
    EudraCT number
    		 2010-020338-25
    Trial protocol
    		 LT   ES   BE   FR   HU   NL   CZ   GB   DE   PT   AT   FI   IT   GR   BG   DK   PL  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    08 Jul 2016
    First version publication date
    08 Jul 2016
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    WA25046
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01194570
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    24 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of ocrelizumab compared with placebo in subjects with primary progressive multiple sclerosis (PPMS).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 11 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 58
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Spain: 74
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Czech Republic: 20
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 106
    Country: Number of subjects enrolled
    Germany: 57
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Ukraine: 74
    Country: Number of subjects enrolled
    United States: 101
    Worldwide total number of subjects
    732
    EEA total number of subjects
    465
    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)
    732
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 943 subjects were screened and 732 were randomized into the study, of which 725 received at least one dose of placebo or ocrelizumab. A total of 549 subjects were ongoing with double-blind treatment at the clinical cut-off date (CCOD).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.
    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
    Subjects received placebo infusions matching ocrelizumab infusions of 300 milligram (mg) separated by 14 days, at a schedule interval of 24 weeks.

    Arm title
    		 Ocrelizumab 600 mg
    Arm description
    		 Subjects with PPMS received ocrelizumab administered, at a scheduled interval of every 24 weeks up to at least 120 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ocrelizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received ocrelizumab 600 mg intraveous (IV) as 300 mg infusions separated by 14 days, at a scheduled interval of every 24 weeks.

    Number of subjects in period 1
    		Placebo Ocrelizumab 600 mg
    Started
    244
    488
    Completed
    0
    0
    Not completed
    244
    488
         Physician decision
    2
    6
         Protocol violation
    -
    2
         Death
    1
    3
         Other
    13
    20
         Pregnancy
    1
    1
         Adverse event
    12
    18
         Non-compliance
    2
    2
         Non-compliance with study drug
    2
    2
         Ongoing at CCOD
    162
    387
         Lost to follow-up
    1
    4
         Lack of efficacy
    27
    21
         Withdrawal by subject
    21
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.

    Reporting group title
    Ocrelizumab 600 mg
    Reporting group description
    		 Subjects with PPMS received ocrelizumab administered, at a scheduled interval of every 24 weeks up to at least 120 weeks.

    Reporting group values
    		 Placebo Ocrelizumab 600 mg Total
    Number of subjects
    		 244 488 732
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.4 ± 8.3 44.7 ± 7.9 -
    Gender categorical
    Units: Subjects
        Female
    		 124 237 361
        Male
    		 120 251 371

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.

    Reporting group title
    Ocrelizumab 600 mg
    Reporting group description
    		 Subjects with PPMS received ocrelizumab administered, at a scheduled interval of every 24 weeks up to at least 120 weeks.

    Primary: Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period

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    End point title
    		 Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period
    End point description
    The time to onset of CDP was defined as the time from baseline to the first disability progression, which is confirmed at the next regularly scheduled visit greater than or equal to (>=) 12 weeks (>=84 days) after the initial disability progression. Baseline for the time to onset of CDP is the date of randomisation, independent of the first day of dosing. Disability progression is defined as an increase of >= 1.0 point from baseline EDSS score, if the baseline EDSS value is less than or equal to (<=) 5.5 points (inclusive), or an increase of >=0.5 points, if the baseline EDSS is >5.5 points. ITT population included all randomised subjects in the study. Here, 99999 indicates median, -99999 minimum and 99999 maximum of full range as value observed were censored.
    End point type
    Primary
    End point timeframe
    Up to clinical cut-off date (CCOD) 24 July 2015
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    244
    487 [1]
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [1] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    Statistical analysis title
    		 Time to onset of CDP sustained for 12 weeks
    Statistical analysis description
    Hazard ratios were estimated by stratified Cox regression. Stratified by geographical region (United States [US] vs. rest of the world [ROW]) and age (<= 45, >45 years).
    Comparison groups
    Placebo v Ocrelizumab 600 mg
    Number of subjects included in analysis
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0321
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.98

    Secondary: Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period

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    End point title
    		 Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period
    End point description
    The time to onset of CDP was defined as the time from baseline to the first disability progression, which is confirmed at the next regularly scheduled visit >=24 weeks (>=161 days) after the initial disability progression. Baseline for the time to onset of CDP is the date of randomisation, independent of the first day of dosing. Disability progression is defined as an increase of >= 1.0 point from baseline EDSS score, if the baseline EDSS value is <=5.5 points (inclusive), or an increase of >=0.5 points, if the baseline EDSS is >5.5 points. ITT population included all randomised subjects in the study. Here, 99999 indicates median, -99999 minimum and 99999 maximum of full range as value observed were censored.
    End point type
    Secondary
    End point timeframe
    Up to clinical cut-off date (CCOD) 24 July 2015
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    244
    487 [2]
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [2] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    Statistical analysis title
    		 Time to onset of CDP sustained for 24 weeks
    Statistical analysis description
    Hazard ratios were estimated by stratified Cox regression. Stratified by geographical region (US vs. ROW) and age (<= 45, >45 years).
    Comparison groups
    Placebo v Ocrelizumab 600 mg
    Number of subjects included in analysis
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0365
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.98

    Secondary: Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120

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    End point title
    		 Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120
    End point description
    ITT population included all randomised subjects in the study. Here, n signifies the number of subjects evaluable for the specified category. Here, least square mean is indicating adjusted geometric mean.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 120
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    239 [3]
    473 [4]
    Units: percent change
    least squares mean (confidence interval 95%)
        Change from Baseline at Week 120 (n= 174, 397)
    55.097 (39.855 to 71.999)
    38.933 (29.222 to 49.374)
    Notes
    [3] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    [4] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    Statistical analysis title
    		 T25-FW change from baseline at Week 120
    Statistical analysis description
    Estimates (back-transformed) based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: log(Post-baseline(BL)/BL) = log(BL 25-FTW) + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + log (BL 25-FTW)*Week. Relative reduction was calculated as -Relative change = -(OCR response-Placebo response)/Placebo response*100%. The 95% CI for relative reduction was obtained using the Bootstrap method.
    Comparison groups
    Placebo v Ocrelizumab 600 mg
    Number of subjects included in analysis
    712
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0404 [5]
    Method
    		 Ranked ANCOVA
    Parameter type
    		 Relative Reduction (%)
    Point estimate
    29.337
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.618
         upper limit
    		 51.456
    Notes
    [5] - P-value from a ranked ANCOVA on Percent Change from BL adjusting for rank of BL 25-Foot Timed Walk (25-FTW), Geographical Region (US vs ROW) and Age (<=45, > 45 years); missing observations imputed with LOCF.

    Secondary: Change From Baseline in Total Volume of T2 Lesions at Week 120

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    End point title
    		 Change From Baseline in Total Volume of T2 Lesions at Week 120
    End point description
    ITT population included all randomised subjects in the study. Here, n signifies the number of subjects evaluable for the specified category. Here, least square mean is indicating adjusted geometric mean.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 120
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    234 [6]
    464 [7]
    Units: percent change
    least squares mean (confidence interval 95%)
        % Change from Baseline to Week 120 (n=183, 400)
    7.426 (4.967 to 9.942)
    -3.366 (-4.987 to -1.718)
    Notes
    [6] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    [7] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    Statistical analysis title
    		 Total Volume of T2 Lesions change at Week 120
    Statistical analysis description
    Estimates (back-transformed) are based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: log(Post-BL/BL) = log(BL T2 lesion volume) + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + log (BL T2 lesion volume)*Week.
    Comparison groups
    Ocrelizumab 600 mg v Placebo
    Number of subjects included in analysis
    698
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Ranked ANCOVA
    Parameter type
    		 Ratio of Adjusted Geometric Means
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.876
         upper limit
    		 0.924
    Notes
    [8] - P-value is from ranked ANCOVA on Percent Change from BL adjusting for rank of BL T2 lesion volume, Geographical Region (US vs ROW) and Age (<=45, > 45 years); missing observations imputed with LOCF.

    Secondary: Percent Change in Total Brain Volume From Week 24 to Week 120

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    End point title
    		 Percent Change in Total Brain Volume From Week 24 to Week 120
    End point description
    ITT population included all randomised subjects in the study. Here, least square mean is indicating adjusted mean.
    End point type
    Secondary
    End point timeframe
    From Week 24 to Week 120
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    203 [9]
    407 [10]
    Units: percent change
        least squares mean (confidence interval 95%)
    -1.093 (-1.236 to -0.951)
    -0.902 (-1.004 to -0.799)
    Notes
    [9] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    [10] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    Statistical analysis title
    		 Percent change in total brain volume
    Statistical analysis description
    Estimates are from analysis based on MMRM using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week. Relative reduction was calculated as – Relative change = - (OCR response-Placebo response)/Placebo response*100%. The 95% CI for relative reduction was obtained using Bootstrap method.
    Comparison groups
    Placebo v Ocrelizumab 600 mg
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0206
    Method
    		 MMRM
    Parameter type
    		 Relative Reduction (%)
    Point estimate
    17.475
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.206
         upper limit
    		 29.251

    Secondary: Change in From Baseline Physical Component Summary Score (PCS) SF-36 Health Survey (SF-36) at Week 120

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    End point title
    		 Change in From Baseline Physical Component Summary Score (PCS) SF-36 Health Survey (SF-36) at Week 120
    End point description
    The SF-36v2 is a 36-item, self- reported, generic measure of quality of life that has been widely used in multiple disease areas. It is composed of 8 health domains: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (ME). In brief, scoring for each health domain scale involves (a) recoding item response values, (b) summing recoded response values for all items in a given scale to obtain the scale raw score, (c) transforming scale raw score to a 0−100 score. The PCS score is computed by (a) multiplying each health domain z score by a scale-specific physical factor score coefficient, (b) summing the resulting products, (c) converting the product total to T score. ITT population. Here, n= number of subjects evaluable for the specified category. Here, least square mean is indicating adjusted mean.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 120
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    185 [11]
    384 [12]
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Change at Week 120 (n= 128, 292)
    -1.108 (-2.394 to 0.177)
    -0.731 (-1.655 to 0.193)
    Notes
    [11] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    [12] - Number of subjects analysed is the total subjects who were evaluable for this endpoint.
    Statistical analysis title
    		 SF-36 PCS change from baseline at Week 120
    Statistical analysis description
    Estimates are from analysis based on MMRM using unstructured covariance matrix: Change = Baseline PCS Score + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + Baseline PCS Score*Week.
    Comparison groups
    Placebo v Ocrelizumab 600 mg
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6034
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.377
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.048
         upper limit
    		 1.802
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.725

    Secondary: Number of Subjects With at Least one Adverse Event (AE)

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    End point title
    		 Number of Subjects With at Least one Adverse Event (AE)
    End point description
    AEs included infusion related reactions (IRRs) and serious multiple sclerosis (MS) relapses, but excluded non-serious MS relapses. The safety population includes all subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first infusion up to the study clinical cut-off date 24 July 2015
    End point values
    		 Placebo Ocrelizumab 600 mg
    Number of subjects analysed
    239
    486
    Units: subjects
    215
    462
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first infusion up to the study clinical cut-off date 24 July 2015
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to ocrelizumab was administered as two intravenous infusions separated by 14 days at a schedule interval of 24 weeks in subjects with PPMS.

    Reporting group title
    Ocrelizumab 600 mg
    Reporting group description
    		 Ocrelizumab administered as two IV infusions separated by 14 days at a scheduled interval of every 24 weeks in subjects with PPMS.

    Serious adverse events
    		 Placebo Ocrelizumab 600 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 239 (22.18%)
    99 / 486 (20.37%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of the cervix
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaplastic large-cell lymphoma
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign vaginal neoplasm
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondroma
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant fibrous histiocytoma
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rosai-Dorfman syndrome
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Bronchopneumonia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 239 (0.00%)
    5 / 486 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative fever
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 239 (0.84%)
    5 / 486 (1.03%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Primary progressive multiple sclerosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paralysis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus allergic
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 239 (0.42%)
    4 / 486 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 239 (0.84%)
    6 / 486 (1.23%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 239 (0.84%)
    5 / 486 (1.03%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 239 (1.26%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendictis
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess of eyelid
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pericarditis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ocrelizumab 600 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    179 / 239 (74.90%)
    400 / 486 (82.30%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    61 / 239 (25.52%)
    191 / 486 (39.30%)
         occurrences all number
    145
    480
    Contusion
         subjects affected / exposed
    19 / 239 (7.95%)
    14 / 486 (2.88%)
         occurrences all number
    22
    19
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 239 (3.77%)
    25 / 486 (5.14%)
         occurrences all number
    9
    25
    Nervous system disorders
    Headache
         subjects affected / exposed
    32 / 239 (13.39%)
    65 / 486 (13.37%)
         occurrences all number
    46
    97
    Dizziness
         subjects affected / exposed
    10 / 239 (4.18%)
    25 / 486 (5.14%)
         occurrences all number
    13
    30
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    23 / 239 (9.62%)
    27 / 486 (5.56%)
         occurrences all number
    31
    29
    Oedema peripheral
         subjects affected / exposed
    12 / 239 (5.02%)
    24 / 486 (4.94%)
         occurrences all number
    14
    26
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 239 (5.02%)
    23 / 486 (4.73%)
         occurrences all number
    14
    26
    Nausea
         subjects affected / exposed
    16 / 239 (6.69%)
    19 / 486 (3.91%)
         occurrences all number
    20
    21
    Diarrhoea
         subjects affected / exposed
    12 / 239 (5.02%)
    22 / 486 (4.53%)
         occurrences all number
    15
    36
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 239 (3.35%)
    29 / 486 (5.97%)
         occurrences all number
    8
    36
    Psychiatric disorders
    Depression
         subjects affected / exposed
    30 / 239 (12.55%)
    37 / 486 (7.61%)
         occurrences all number
    33
    38
    Insomnia
         subjects affected / exposed
    12 / 239 (5.02%)
    27 / 486 (5.56%)
         occurrences all number
    12
    30
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    36 / 239 (15.06%)
    55 / 486 (11.32%)
         occurrences all number
    50
    65
    Arthralgia
         subjects affected / exposed
    21 / 239 (8.79%)
    38 / 486 (7.82%)
         occurrences all number
    28
    43
    Pain in extremity
         subjects affected / exposed
    25 / 239 (10.46%)
    32 / 486 (6.58%)
         occurrences all number
    34
    35
    Musculoskeletal pain
         subjects affected / exposed
    12 / 239 (5.02%)
    19 / 486 (3.91%)
         occurrences all number
    12
    23
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    65 / 239 (27.20%)
    110 / 486 (22.63%)
         occurrences all number
    117
    184
    Urinary tract infection
         subjects affected / exposed
    53 / 239 (22.18%)
    96 / 486 (19.75%)
         occurrences all number
    114
    214
    Influenza
         subjects affected / exposed
    21 / 239 (8.79%)
    56 / 486 (11.52%)
         occurrences all number
    24
    69
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 239 (5.86%)
    53 / 486 (10.91%)
         occurrences all number
    21
    72
    Bronchitis
         subjects affected / exposed
    12 / 239 (5.02%)
    29 / 486 (5.97%)
         occurrences all number
    18
    36
    Gastroenteritis
         subjects affected / exposed
    12 / 239 (5.02%)
    20 / 486 (4.12%)
         occurrences all number
    15
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2011
    1. Clarification of the implementation of 2 separate infusions 14 days apart throughout the study. Implementation of the amended re-treatment regimen consisting of two 300 mg ocrelizumab infusions administered 14 days apart at a scheduled interval of every 24 weeks for all treatment doses of Study WA25046. 2. Revision of inclusion / exclusion criteria. The main changes included: 1) the inclusion of subjects with higher age (<=55 years) for a broader PPMS study population and 2) modification of the exclusion criteria to reduce the potential risk of infection to study subjects and to improve clarity of screening criteria. 3. Clarifications on prior experience with ocrelizumab development programs in lupus, rheumatoid arthritis (RA) and relapsing-remitting multiple sclerosis (RRMS).
    15 Jun 2012
    1. Dosing preparation and infusion guidance were revised to simplify the preparation of infusion bags and dosing procedures. 2. Specific eligibility cut-off values for immunoglobulin M (IgM) and immunoglobulin G (IgG) were modified to reflect the central lab reference ranges. 3. Sites were informed of additional, optional sub-studies conducted at select centers in which subjects could be eligible to participate.
    06 Feb 2015
    1. An update to the Statistical Considerations and Analytical Plan section of the protocol in line with the Statistical Analysis Plan (SAP) for the study. 2. Conversion of optional investigator-sponsored Roche-supported sub-studies to Roche supported exploratory substudies as per current policy of the sponsor. 3. Revision of the pre-specified mandatory biomarker analysis plan. 4. Inclusion of more detail with respect to the open-label extension phase.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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