Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

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

    Summary
    EudraCT number
    2010-020337-99
    Trial protocol
    GB   FR   CZ   LV   HU   FI   DE   BE   SK   AT   NL   LT   EE   PT   BG   ES   PL   IT  
    Global end of trial date
    31 Dec 2022

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Jan 2024
    First version publication date
    03 Jun 2016
    Other versions
    v1
    Version creation reason

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    WA21092
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01247324
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4070
    Public contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +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
    31 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of ocrelizumab compared with interferon beta-1a 44 mcg subcutaneous (SC) in patients with relapsing multiple sclerosis (RMS).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Aug 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    11 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Czechia: 130
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Estonia: 16
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Lithuania: 17
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Peru: 22
    Country: Number of subjects enrolled
    Poland: 69
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Russian Federation: 67
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Tunisia: 8
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    United States: 210
    Country: Number of subjects enrolled
    South Africa: 4
    Worldwide total number of subjects
    821
    EEA total number of subjects
    405
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    821
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1051 participants were screened for entry into the study. 821 participants were entered into the double-blind treatment period. Participants who completed the 96-week double-blind treatment had an option to enter a single group, active treatment open label extension, providing they fulfilled the eligibility criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Interferon Beta-1a + Placebo
    Arm description
    Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).
    Arm type
    Active comparator

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

    Arm title
    Ocrelizumab + Placebo
    Arm description
    Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
    Arm type
    Experimental

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

    Number of subjects in period 1
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Started
    411
    410
    Completed
    226
    239
    Not completed
    185
    171
         Physician decision
    2
    3
         Study Terminated by Sponsor
    4
    1
         Reason not specified
    42
    32
         Consent withdrawn by participant
    41
    56
         Missing
    2
    1
         Adverse event, non-fatal
    49
    35
         Death
    6
    10
         Pregnancy
    5
    10
         Non-compliance with study drug
    3
    -
         Non-compliance
    3
    2
         Lost to follow-up
    3
    6
         Lack of efficacy
    24
    14
         Protocol deviation
    1
    1

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Interferon Beta-1a + Placebo
    Reporting group description
    Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).

    Reporting group title
    Ocrelizumab + Placebo
    Reporting group description
    Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.

    Reporting group values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo Total
    Number of subjects
    411 410 821
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    411 410 821
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    36.9 ( 9.3 ) 37.1 ( 9.3 ) -
    Gender, Male/Female
    Units:
        Female
    272 270 542
        Male
    139 140 279
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    1 0 1
        Black or African American
    12 19 31
        White
    375 375 750
        Other
    14 10 24
        Multiple
    9 5 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    58 44 102
        Not Hispanic or Latino
    318 329 647
        Not Stated
    35 37 72
    Subject analysis sets

    Subject analysis set title
    Interferon Beta-1a + Placebo (Open Label Extension)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

    Subject analysis set title
    Ocrelizumab + Placebo (Open Label Extension)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

    Subject analysis sets values
    Interferon Beta-1a + Placebo (Open Label Extension) Ocrelizumab + Placebo (Open Label Extension)
    Number of subjects
    326
    352
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.24 ( 9.31 )
    39.30 ( 9.36 )
    Gender, Male/Female
    Units:
        Female
        Male
    Race
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Black or African American
        White
        Other
        Multiple
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Not Stated

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Interferon Beta-1a + Placebo
    Reporting group description
    Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).

    Reporting group title
    Ocrelizumab + Placebo
    Reporting group description
    Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.

    Subject analysis set title
    Interferon Beta-1a + Placebo (Open Label Extension)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

    Subject analysis set title
    Ocrelizumab + Placebo (Open Label Extension)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

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

    Close Top of page
    End point title
    Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks
    End point description
    ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.
    End point type
    Primary
    End point timeframe
    Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: relapses/participant year of treatment
        number (confidence interval 95%)
    0.292 (0.235 to 0.361)
    0.156 (0.122 to 0.200)
    Statistical analysis title
    ARR by Week 96
    Statistical analysis description
    Adjusted by Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Rate Ratio
    Point estimate
    0.536
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.719

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

    Close Top of page
    End point title
    Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period
    End point description
    Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment. Here, 99999 indicates median and -99999 and 99999 minimum and maximum of full range as less than 50% of subjects experience onset of CDP.
    End point type
    Secondary
    End point timeframe
    Week 108
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    Time to onset CDP at week 12
    Statistical analysis description
    Time to onset CDP at week 12
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0139
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    0.9

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

    Close Top of page
    End point title
    Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment
    End point description
    The total number of T1 gadolinium-enhancing lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: lesions
    337
    21
    Statistical analysis title
    T1-Gd lesions
    Statistical analysis description
    Adjusted by baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. ROW).
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.032
         upper limit
    0.104

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

    Close Top of page
    End point title
    Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
    End point description
    The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: lesions
    1916
    430
    Statistical analysis title
    Enlarging T2 hyperintense lesions
    Statistical analysis description
    Adjusted by baseline T2 lesion count, baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. ROW).
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.229
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.174
         upper limit
    0.3

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

    Close Top of page
    End point title
    Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks
    End point description
    Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    306
    310
    Units: percentage of participants
        number (confidence interval 95%)
    12.42 (8.94 to 16.64)
    20.00 (15.69 to 24.89)
    Statistical analysis title
    Confirmed Disability Improvement for 12 weeks
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) Chi-Squared test was used, stratified by Geographical Region (US vs. Rest of World) and Baseline EDSS (<4.0 vs. >=4.0). 95 percent (%) confidence interval (CI) of proportion was constructed using Pearson-Clopper method.
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0106
    Method
    CMH Chi-Squared test (stratified)
    Parameter type
    Relative risk (stratified)
    Point estimate
    1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.11
         upper limit
    2.33

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

    Close Top of page
    End point title
    Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period
    End point description
    Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from baseline EDSS score when baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from baseline EDSS score when baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when increase in EDSS was confirmed at a regularly scheduled visit at least 24 weeks after initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at date of their last EDSS assessment. Here, 99999 indicates median and -99999 and 99999 min & max of full range as less than 50% of subjects experience onset of CDP.
    End point type
    Secondary
    End point timeframe
    Week 108
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    Time to onset CDP at week 24
    Statistical analysis description
    Hazard ratios (HR) were estimated by stratified Cox regression. Stratification factors were Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0278
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.95

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

    Close Top of page
    End point title
    Number of T1 Hypointense Lesions During the Double-Blind Treatment
    End point description
    The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) for all participants in the treatment group was calculated as the sum of the individual number of new lesions at Weeks 24, 48, and 96.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: lesions
    1307
    564
    Statistical analysis title
    T1-Gd lesions
    Statistical analysis description
    Adjusted by baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. ROW).
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Negative Binomial Model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.428
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.328
         upper limit
    0.557

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

    Close Top of page
    End point title
    Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96
    End point description
    MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-HPT); and C) Paced Auditory Serial Addition Test (PASAT-3 version). The MSFCS is based on the concept that scores for these three dimensions (arm, leg, and cognitive function) are combined to create a single score (the MSFC) that can be used to detect change over time in a group of participants with MS. Since the three primary measures differ in what they actually measure, a common composite score for the three different measures i.e., Z- score was selected for the purpose. MSFC Score = {Z arm, average + Z leg, average + Z cognitive} / 3.0. The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each participant at each time point. A score of +1 indicates that, on average, an individual scored 1 standard deviation (SD) better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: Z-score
    arithmetic mean (standard error)
        Unadjusted Baseline mean (n= 359, 360)
    0.028 ( 0.034 )
    -0.012 ( 0.040 )
        Adjusted Week 96 mean (n= 308, 322)
    0.174 ( 0.031 )
    0.213 ( 0.031 )
    Statistical analysis title
    MSFC score baseline to week 96
    Statistical analysis description
    Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Change = Baseline MSFCS Score + Geographical Region + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Baseline MSFCS Score*Week.
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3261
    Method
    mixed-effect model of repeated measures
    Parameter type
    Difference in Adjusted Means
    Point estimate
    0.039
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.039
         upper limit
    0.116
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039

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

    Close Top of page
    End point title
    Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96
    End point description
    Brain volume was recorded as an absolute "normalized" value at the baseline visit then recorded at subsequent visits as a percentage change relative to the absolute value at the baseline visit. Therefore, brain volume at Week 24 was calculated as the brain volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from baseline visit to Week 24]/100). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week.
    End point type
    Secondary
    End point timeframe
    From Week 24 up to Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    267
    281
    Units: percent change
        arithmetic mean (standard error)
    -0.741 ( 0.046 )
    -0.572 ( 0.044 )
    Statistical analysis title
    Percent change in brain volume
    Statistical analysis description
    Estimates are from analysis based on MMRM using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment +Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week.
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0042
    Method
    mixed-effect model of repeated measures
    Parameter type
    Difference in Adjusted Means
    Point estimate
    0.168
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.053
         upper limit
    0.283
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058

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

    Close Top of page
    End point title
    Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96
    End point description
    The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t- scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    411
    410
    Units: t-score
    arithmetic mean (standard error)
        Unadjusted Baseline mean (n= 338, 357)
    45.399 ( 0.529 )
    45.065 ( 0.507 )
        Adjusted mean change at week 96 (n= 276, 315)
    -0.657 ( 0.475 )
    0.036 ( 0.456 )
    Statistical analysis title
    SF-36 PCS score at week 96
    Statistical analysis description
    Estimates are from analysis based on MMRM using unstructured covariance matrix: Change = Baseline PCS Score + Geographical Region + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Baseline PCS Score*Week.
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2193
    Method
    mixed-effect model of repeated measures
    Parameter type
    Difference in Adjusted Means
    Point estimate
    0.693
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.414
         upper limit
    1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.564

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

    Close Top of page
    End point title
    Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96
    End point description
    NEDA was defined only for participants with a baseline EDSS score >=2.0. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Participants who completed the 96- week treatment period were considered as having evidence of disease activity if at least one protocol- defined relapse (PDR), a confirmed disability progression (CDP) event or at least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise the participant was considered as having NEDA.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    291
    289
    Units: percentage of participants
        number (confidence interval 95%)
    27.1 (22.1 to 32.6)
    47.4 (41.5 to 53.3)
    Statistical analysis title
    NEDA at week 96
    Statistical analysis description
    Analysed using CMH test, stratified by Geographical Region (US vs. Rest of World) and Baseline EDSS (<4.0 vs. >=4.0). 95% CI of proportion was constructed using Pearson-Clopper method
    Comparison groups
    Interferon Beta-1a + Placebo v Ocrelizumab + Placebo
    Number of subjects included in analysis
    580
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    CMH Chi-Squared test (stratified)
    Parameter type
    Relative risk (stratified)
    Point estimate
    1.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.39
         upper limit
    2.17

    Secondary: Number of Participants With Adverse Events (AEs)

    Close Top of page
    End point title
    Number of Participants With Adverse Events (AEs)
    End point description
    AEs included infusion related reactions (IRRs) and serious MS relapses, but excluded non-serious MS relapses. Serious Adverse Events (SAEs) included serious MS relapses and serious IRRs. The safety population included all subjects who received any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 588 weeks
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo Interferon Beta-1a + Placebo (Open Label Extension) Ocrelizumab + Placebo (Open Label Extension)
    Number of subjects analysed
    409
    408
    326
    352
    Units: Participants
    331
    327
    302
    319
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC) [1]
    End point description
    AUC represents total drug exposure for one dosing interval after the 4th dose.
    End point type
    Secondary
    End point timeframe
    Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint did not have statistical analyses performed.
    End point values
    Ocrelizumab + Placebo
    Number of subjects analysed
    393
    Units: micrograms per milliliter*day
        arithmetic mean (standard deviation)
    3513 ( 955 )
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab
    End point description
    Number of participants positive for anti-drug antibodies (ADAs) to ocrelizumab is the number of post- baseline evaluable participants determined to have treatment-induced ADA or treatment-enhanced ADA during the study period.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 96
    End point values
    Interferon Beta-1a + Placebo Ocrelizumab + Placebo
    Number of subjects analysed
    409
    408
    Units: Participants
        Positive sample at baseline (n= 397, 396)
    2
    1
        Positive for ADA post-baseline (n= 401, 402)
    2
    1
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From baseline to approximately 588 weeks
    Adverse event reporting additional description
    The safety population includes all enrolled patients who have received at least one dose of any study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Interferon Beta- 1a + Placebo (Double Blind Period)
    Reporting group description
    Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).

    Reporting group title
    Ocrelizumab + Placebo (Double Blind Period)
    Reporting group description
    Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.

    Reporting group title
    Interferon Beta-1a + Placebo (Open Label Extension)
    Reporting group description
    During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

    Reporting group title
    Ocrelizumab + Placebo (Open Label Extension)
    Reporting group description
    During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

    Serious adverse events
    Interferon Beta- 1a + Placebo (Double Blind Period) Ocrelizumab + Placebo (Double Blind Period) Interferon Beta-1a + Placebo (Open Label Extension) Ocrelizumab + Placebo (Open Label Extension)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 409 (7.82%)
    28 / 408 (6.86%)
    109 / 326 (33.44%)
    116 / 352 (32.95%)
         number of deaths (all causes)
    1
    0
    6
    11
         number of deaths resulting from adverse events
    0
    0
    6
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
    2 / 326 (0.61%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST NEOPLASM
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL CANCER
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CERVIX CARCINOMA STAGE II
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL ADENOCARCINOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DERMATOFIBROSARCOMA PROTUBERANS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL ADENOCARCINOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    BREAST CANCER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLON CANCER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAPILLARY THYROID CANCER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 408 (0.00%)
    3 / 326 (0.92%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLESTEATOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MANTLE CELL LYMPHOMA
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGIOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INVASIVE BREAST CARCINOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SALIVARY GLAND ADENOMA
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    VARICOSE VEIN
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    MAMMOPLASTY
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    CERVICAL INCOMPETENCE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANEMBRYONIC GESTATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PRE-ECLAMPSIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABORTION SPONTANEOUS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    5 / 352 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLAMMATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    PROSTATITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSMENORRHOEA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENITAL PROLAPSE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEAVY MENSTRUAL BLEEDING
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENOPAUSAL SYMPTOMS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CERVICAL POLYP
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CYST
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABNORMAL UTERINE BLEEDING
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL HYPERTROPHY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CYST RUPTURED
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE PROLAPSE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENORRHAGIA
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    SINUS CONGESTION
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERVENTILATION
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASTHMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NASAL SEPTUM DEVIATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    4 / 326 (1.23%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PSYCHOGENIC TREMOR
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AFFECTIVE DISORDER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMPLETED SUICIDE
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    ANXIETY
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    DEVICE DISLOCATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    PORTAL VEIN THROMBOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIVER DISORDER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIVER INJURY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GALLBLADDER MUCOCOELE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS CHRONIC
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    TENDON DISLOCATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVERDOSE
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCLE RUPTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROCEDURAL PAIN
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CRANIOCEREBRAL INJURY
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONCUSSION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MULTIPLE INJURIES
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACETABULUM FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FOOT FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCLE STRAIN
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST LUMBAR PUNCTURE SYNDROME
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TIBIA FRACTURE
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAND FRACTURE
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMMINUTED FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIPROSTHETIC FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ALCOHOL POISONING
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TENDON RUPTURE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FRACTURE DISPLACEMENT
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    HYPERTROPHIC CARDIOMYOPATHY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PHIMOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    CORONARY ARTERY OCCLUSION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    3 / 326 (0.92%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    4 / 352 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    4 / 352 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POLYNEUROPATHY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MIGRAINE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARPAL TUNNEL SYNDROME
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARTIAL SEIZURES WITH SECONDARY GENERALISATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 408 (0.25%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRIGEMINAL NEURALGIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYELOPATHY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FACIAL PARESIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RUPTURED CEREBRAL ANEURYSM
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CERVICAL RADICULOPATHY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MULTIPLE SCLEROSIS RELAPSE
         subjects affected / exposed
    3 / 409 (0.73%)
    0 / 408 (0.00%)
    3 / 326 (0.92%)
    5 / 352 (1.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSARTHRIA
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 408 (0.49%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APHASIA
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VESTIBULAR DISORDER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RETINAL ARTERY OCCLUSION
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UVEITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CATARACT
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CROHN'S DISEASE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL INFLAMMATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRA-ABDOMINAL FLUID COLLECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC PERFORATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL INCARCERATED HERNIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IMPAIRED GASTRIC EMPTYING
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FUNCTIONAL GASTROINTESTINAL DISORDER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINAL STENOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PEPTIC ULCER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYTHEMA NODOSUM
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIDRADENITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL DISCOMFORT
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RHABDOMYOLYSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL RETROLISTHESIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JAW CYST
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THORACIC SPINAL STENOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTHRALGIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRIGGER FINGER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMARTHROSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CERVICAL SPINAL STENOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIORBITAL CELLULITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SALPINGITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SALPINGO-OOPHORITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENCEPHALITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTIVE THROMBOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    6 / 326 (1.84%)
    8 / 352 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
    CHRONIC SINUSITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST-ACUTE COVID-19 SYNDROME
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SINUSITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MASTOIDITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY SYNCYTIAL VIRUS INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIRECTAL ABSCESS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROBORRELIOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUBERCULOSIS BLADDER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    4 / 326 (1.23%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY SEPSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BILIARY SEPSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 409 (0.24%)
    2 / 408 (0.49%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS PERFORATED
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS INFECTIVE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TOOTH ABSCESS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PILONIDAL DISEASE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUBO-OVARIAN ABSCESS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DENGUE FEVER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY TUBERCULOSIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    3 / 352 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    17 / 326 (5.21%)
    20 / 352 (5.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 18
    6 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    1 / 5
    SEPTIC ARTHRITIS STAPHYLOCOCCAL
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    11 / 326 (3.37%)
    6 / 352 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 16
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES SIMPLEX
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYSTEMIC CANDIDA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES SIMPLEX MENINGITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INJECTION SITE CELLULITIS
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTED DERMAL CYST
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL ABSCESS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOCARDITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYME DISEASE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    2 / 326 (0.61%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABSCESS LIMB
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENITAL HERPES SIMPLEX
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 408 (0.25%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC INFLAMMATORY DISEASE
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    GLUCOSE TOLERANCE IMPAIRED
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERNATRAEMIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    1 / 326 (0.31%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TYPE 2 DIABETES MELLITUS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Interferon Beta- 1a + Placebo (Double Blind Period) Ocrelizumab + Placebo (Double Blind Period) Interferon Beta-1a + Placebo (Open Label Extension) Ocrelizumab + Placebo (Open Label Extension)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    303 / 409 (74.08%)
    264 / 408 (64.71%)
    285 / 326 (87.42%)
    286 / 352 (81.25%)
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    31 / 409 (7.58%)
    126 / 408 (30.88%)
    83 / 326 (25.46%)
    71 / 352 (20.17%)
         occurrences all number
    47
    236
    172
    179
    FALL
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    19 / 326 (5.83%)
    8 / 352 (2.27%)
         occurrences all number
    0
    0
    22
    11
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    23 / 326 (7.06%)
    20 / 352 (5.68%)
         occurrences all number
    0
    0
    24
    23
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    53 / 409 (12.96%)
    33 / 408 (8.09%)
    46 / 326 (14.11%)
    40 / 352 (11.36%)
         occurrences all number
    62
    52
    57
    47
    MULTIPLE SCLEROSIS RELAPSE
         subjects affected / exposed
    132 / 409 (32.27%)
    90 / 408 (22.06%)
    82 / 326 (25.15%)
    84 / 352 (23.86%)
         occurrences all number
    206
    133
    163
    158
    PARAESTHESIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    17 / 326 (5.21%)
    18 / 352 (5.11%)
         occurrences all number
    0
    0
    28
    23
    HYPOAESTHESIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    19 / 326 (5.83%)
    16 / 352 (4.55%)
         occurrences all number
    0
    0
    40
    23
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    24 / 326 (7.36%)
    25 / 352 (7.10%)
         occurrences all number
    0
    0
    35
    29
    FATIGUE
         subjects affected / exposed
    29 / 409 (7.09%)
    21 / 408 (5.15%)
    34 / 326 (10.43%)
    36 / 352 (10.23%)
         occurrences all number
    33
    22
    52
    45
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    85 / 409 (20.78%)
    14 / 408 (3.43%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences all number
    97
    14
    0
    0
    INJECTION SITE ERYTHEMA
         subjects affected / exposed
    73 / 409 (17.85%)
    0 / 408 (0.00%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences all number
    75
    0
    0
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    22 / 326 (6.75%)
    16 / 352 (4.55%)
         occurrences all number
    0
    0
    25
    18
    NAUSEA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    12 / 326 (3.68%)
    19 / 352 (5.40%)
         occurrences all number
    0
    0
    13
    22
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    26 / 326 (7.98%)
    30 / 352 (8.52%)
         occurrences all number
    0
    0
    32
    46
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    19 / 326 (5.83%)
    8 / 352 (2.27%)
         occurrences all number
    0
    0
    23
    12
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    15 / 409 (3.67%)
    21 / 408 (5.15%)
    0 / 326 (0.00%)
    0 / 352 (0.00%)
         occurrences all number
    15
    22
    0
    0
    ANXIETY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    15 / 326 (4.60%)
    23 / 352 (6.53%)
         occurrences all number
    0
    0
    17
    28
    DEPRESSION
         subjects affected / exposed
    26 / 409 (6.36%)
    27 / 408 (6.62%)
    24 / 326 (7.36%)
    45 / 352 (12.78%)
         occurrences all number
    26
    31
    28
    55
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    20 / 409 (4.89%)
    24 / 408 (5.88%)
    32 / 326 (9.82%)
    36 / 352 (10.23%)
         occurrences all number
    24
    27
    40
    46
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    19 / 326 (5.83%)
    11 / 352 (3.13%)
         occurrences all number
    0
    0
    24
    12
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    27 / 326 (8.28%)
    24 / 352 (6.82%)
         occurrences all number
    0
    0
    34
    34
    ARTHRALGIA
         subjects affected / exposed
    30 / 409 (7.33%)
    27 / 408 (6.62%)
    46 / 326 (14.11%)
    29 / 352 (8.24%)
         occurrences all number
    35
    31
    57
    43
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    19 / 326 (5.83%)
    15 / 352 (4.26%)
         occurrences all number
    0
    0
    24
    15
    SINUSITIS
         subjects affected / exposed
    25 / 409 (6.11%)
    18 / 408 (4.41%)
    41 / 326 (12.58%)
    49 / 352 (13.92%)
         occurrences all number
    28
    22
    68
    75
    BRONCHITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    46 / 326 (14.11%)
    51 / 352 (14.49%)
         occurrences all number
    0
    0
    65
    91
    HERPES ZOSTER
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    18 / 326 (5.52%)
    13 / 352 (3.69%)
         occurrences all number
    0
    0
    20
    18
    INFLUENZA
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    30 / 326 (9.20%)
    24 / 352 (6.82%)
         occurrences all number
    0
    0
    33
    30
    NASOPHARYNGITIS
         subjects affected / exposed
    40 / 409 (9.78%)
    42 / 408 (10.29%)
    68 / 326 (20.86%)
    73 / 352 (20.74%)
         occurrences all number
    52
    60
    138
    156
    CONJUNCTIVITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    11 / 326 (3.37%)
    19 / 352 (5.40%)
         occurrences all number
    0
    0
    11
    26
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    35 / 409 (8.56%)
    59 / 408 (14.46%)
    89 / 326 (27.30%)
    90 / 352 (25.57%)
         occurrences all number
    44
    82
    181
    182
    COVID-19
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    96 / 326 (29.45%)
    96 / 352 (27.27%)
         occurrences all number
    0
    0
    117
    110
    GASTROENTERITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    18 / 326 (5.52%)
    16 / 352 (4.55%)
         occurrences all number
    0
    0
    22
    25
    CYSTITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    21 / 326 (6.44%)
    16 / 352 (4.55%)
         occurrences all number
    0
    0
    25
    21
    ORAL HERPES
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    18 / 326 (5.52%)
    21 / 352 (5.97%)
         occurrences all number
    0
    0
    59
    63
    PHARYNGITIS
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    17 / 326 (5.21%)
    16 / 352 (4.55%)
         occurrences all number
    0
    0
    20
    23
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    24 / 326 (7.36%)
    24 / 352 (6.82%)
         occurrences all number
    0
    0
    29
    31
    URINARY TRACT INFECTION
         subjects affected / exposed
    56 / 409 (13.69%)
    52 / 408 (12.75%)
    80 / 326 (24.54%)
    101 / 352 (28.69%)
         occurrences all number
    81
    92
    236
    296
    VIRAL INFECTION
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 408 (0.00%)
    19 / 326 (5.83%)
    17 / 352 (4.83%)
         occurrences all number
    0
    0
    32
    24

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2011
    Study design was changed from rater blind to double blind, double dummy design to improve robustness of the study. - 400 mg dose of ocrelizumab was removed leaving a single dose of ocrelizumab 600 mg; therefore total number of patients was decreased from 1200 to 800 - eligibility criteria was amended to further characterize benefits of treatment with ocrelizumab in wide range of patients with different disease activity and severity of RMS. - screening period has been decreased from 4 weeks to 2 weeks -Biomarkers DNA sampling was added to protocol to identify dynamic biomarkers that are predictive of response to ocrelizumab treatment - Karnofsky Performance Scale, Low Contrast Vision Acuity testing and Symbol Digit Modality Test were implemented to support assessment of disability and to facilitate evaluation of benefit risk profile of ocrelizumab. -open-label extension phase of study will be conducted as separate extension study under new protocol.
    15 Jun 2012
    Protocol was amended to provide greater clarity in protocol language around expedited reporting of SAEs - Revised dosing preparation and infusion guidance to simplify procedures - Refined some aspects of inclusion/exclusion criteria -Refined several operational aspects of the study conduct -Informed sites of additional, optional sub-studies conducted at select centers in which patients in this trial may be eligible to participate
    14 Mar 2013
    Protocol amended to include an Open-Label Extension Phase and clarify how sustained disability progression is calculated. - Provided Sponsor update on anti-CD20 therapies - added exploratory objective: Proportion of disease activity free patients, defined as absence of both relapses and sustained accumulation of disability, and absence of magnetic resonance imaging (MRI) activity by Week 96 - amended wording for premature withdrawal - updated Medical Monitor responsible for the trial
    04 Sep 2014
    An update to the Statistical Considerations and Analytical Plan section of the protocol in line with the Statistical Analysis Plan (SAP) for the study. - Optional investigator-sponsored Roche-supported exploratory sub-studies being conducted at selected sites have been converted to Roche-sponsored studies as per current policy of the sponsor. - Mandatory biomarker analysis plan was revised and will include but is not limited to interleukin-6; the B-cell activating factor (BAFF) and Complement Factor H (CFH) will not be analyzed. - Inclusion of ocrelizumab concentration sample during the open label extension phase of the study. - Optional Roche Clinical Repository Sampling (RCR sampling) has now been discontinued from the open-label extension and safety follow-up phases of the study. -Local versions of WA21092 protocol (UK, GER) was consolidated into main body of revised protocol - WA21092 Coordinating Investigator for study was specified in protocol - Various minor changes and clarifications was made to improve clarity and consistency of protocol
    04 Mar 2016
    Clarification of the following: 1. objectives of the open-label extension (OLE) phase, 2. permittance of alternative MS treatments and prolongation of safety follow-up period for patients switching to other MS therapies post-ocrelizumab, 3. Patient Agreement for Continuation in the Study in Case of Confirmed Disability Progression, 4. duration of OLE phase. 5. schedule of assessments in OLE phase of study to improve consistency and data collection - Voluntary collection of pregnancy outcomes and infant health information on first year of life. - Update to telephone interview script. - Visual Evoked Potential (VEP) assessments in the OCT sub-study schedule of assessments have been amended - A change in version of ocrelizumab that will be administered across programme has been detailed in protocol.
    04 Oct 2017
    The protocol safety wording was substantially amended. - Additional wording changes were made to align with the most recent version of the core safety text. - Addition of Adverse Events of Special Interest (AESI) - Requirement for antihistamines pre-treatment -Removal of contraception requirements for male patients and female partner reporting - Changes to contraception requirements, duration of contraception, and procedures for pregnant women during the OLE - End of study for optical coherence tomography exploratory substudy
    03 Aug 2018
    Addition of optional collection of biosamples for the Research Biosample Repository taken at a single timepoint during the OLE Phase - Extension of the WA21092 OLE treatment phase to 31 December 2020 - Updated language pertaining to impairment of vaccination response -Clarification regarding re-treatment with ocrelizumab for patients with active tuberculosis (TB) and for pregnant or breastfeeding female patients - Addition of information regarding exposure in utero to ocrelizumab and vaccination of neonates and infants with live or live-attenuated viruses.
    18 Dec 2019
    The WA21092 OLE treatment phase has been extended to 31 December 2022 - The safety risks for ocrelizumab have been updated - The pharmacokinetic/human anti-human antibody (HAHA) collection/analysis has been removed - The plasma and urine sample collections for John Cunningham virus (JCV) have been removed - Guidance for diagnosis of PML has been updated - Guidance for reporting abortions has been updated - Reference to Medical Monitor has been changed where applicable and the emergency contact information has been updated - Language has been added to clarify that, after withdrawal of consent for participation in the Research Biosample Repository (RBR), remaining RBR samples will be destroyed or will no longer be linked to the patient
    27 Jul 2020
    Protocol was amended to incorporate the option of a shorter study drug infusion regimen - shorter infusion regimen of 2 hours (about 3.5 to 4 hours in total)
    19 Nov 2021
    Introduced the option of a rollover study (MN43964), into which all ongoing participants can enroll during the course of 2022. -a reduction in the safety follow-up period and the incorporation of the risk assessment of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the participant population were implemented in the protocol

    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
    For support, Contact us.
    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.

    European Medicines Agency © 1995-Fri May 02 19:11:07 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA