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    Clinical Trial Results:
    A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis

    Summary
    EudraCT number
    		 2008-004753-14
    Trial protocol
    		 BE   CZ   SK   DE   IE   LV   ES   FR   EE   GR   AT   NL   BG   IT   GB  
    Global end of trial date
    08 Nov 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Feb 2021
    First version publication date
    06 Nov 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00835770
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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
    08 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the long-term safety profile of BG00012.
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 308
    Country: Number of subjects enrolled
    United States: 267
    Country: Number of subjects enrolled
    India: 162
    Country: Number of subjects enrolled
    Germany: 160
    Country: Number of subjects enrolled
    Ukraine: 104
    Country: Number of subjects enrolled
    Czechia: 98
    Country: Number of subjects enrolled
    Serbia: 86
    Country: Number of subjects enrolled
    France: 69
    Country: Number of subjects enrolled
    Belgium: 41
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    Mexico: 38
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Australia: 26
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Moldova, Republic of: 24
    Country: Number of subjects enrolled
    Romania: 23
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Belarus: 20
    Country: Number of subjects enrolled
    Estonia: 19
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    North Macedonia: 19
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 15
    Country: Number of subjects enrolled
    Croatia: 14
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    Switzerland: 14
    Country: Number of subjects enrolled
    Latvia: 11
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Guatemala: 5
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Puerto Rico: 3
    Worldwide total number of subjects
    1738
    EEA total number of subjects
    862
    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)
    1738
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 298 investigative sites from 03 February 2009 to 08 November 2019.

    Pre-assignment
    Screening details
    		 The study included subjects who completed studies 2006-003696-12 and 2006-003697-10. A total of 1736 subjects were treated in the open-label phase extension study 2008-004753-14, out of which 759 completed the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BG00012 240 mg BID
    Arm description
    		 Subjects received BG00012 240 milligrams (mg) (120 mg each) 2 capsules orally, twice a day (BID) and 2 matching placebo capsules once a day (QD) up to 8 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    Other name
    Dimethly fumarate
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received BG00012 240 mg (120 mg each) 2 capsules orally, BID up to 8 years.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 2 matching placebo to BG00012 capsules QD up to 8 years.

    Arm title
    		 BG00012 240 mg TID
    Arm description
    		 Subjects received BG00012 240 mg (120 mg each) 2 capsules orally, three times a day (TID) up to 8 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    Other name
    Dimethly fumarate
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received BG00012 240 mg (120 mg each) 2 capsules orally, TID up to 8 years.

    Number of subjects in period 1 [1]
    		BG00012 240 mg BID BG00012 240 mg TID
    Started
    868
    868
    Completed
    384
    375
    Not completed
    484
    493
         Subject Non-Compliance
    11
    9
         MS progression
    14
    9
         Adverse Event
    113
    124
         Death
    4
    6
         Not specified
    115
    104
         Unknown
    2
    1
         Investigator decision
    42
    42
         Lost to follow-up
    22
    19
         Consent withdrawn
    144
    156
         MS relapse
    17
    23
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in the baseline period is for intent to treat population (868 subjects in BG00012 240 mg BID, 868 subjects in BG00012 240 mg TID).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BG00012 240 mg BID
    Reporting group description
    		 Subjects received BG00012 240 milligrams (mg) (120 mg each) 2 capsules orally, twice a day (BID) and 2 matching placebo capsules once a day (QD) up to 8 years.

    Reporting group title
    BG00012 240 mg TID
    Reporting group description
    		 Subjects received BG00012 240 mg (120 mg each) 2 capsules orally, three times a day (TID) up to 8 years.

    Reporting group values
    		 BG00012 240 mg BID BG00012 240 mg TID Total
    Number of subjects
    		 868 868 1736
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.6 ( 8.93 ) 40.1 ( 9.23 ) -
    Sex: Female, Male
    Units: subjects
        Female
    		 616 596 1212
        Male
    		 252 272 524
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 285 309 594
        Black or African American
    		 10 16 26
        Asian
    		 82 80 162
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 32 24 56
        Not Reported Due To Confidentiality Regulations
    		 459 439 898

    End points

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    End points reporting groups
    Reporting group title
    BG00012 240 mg BID
    Reporting group description
    		 Subjects received BG00012 240 milligrams (mg) (120 mg each) 2 capsules orally, twice a day (BID) and 2 matching placebo capsules once a day (QD) up to 8 years.

    Reporting group title
    BG00012 240 mg TID
    Reporting group description
    		 Subjects received BG00012 240 mg (120 mg each) 2 capsules orally, three times a day (TID) up to 8 years.

    Subject analysis set title
    BG00012 240 mg BID (Prior BG00012 240 mg BID)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, BID and 2 matching placebo capsules QD for up to 8 years. Subjects who had received BG00012 240 mg BID in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg TID (Prior BG00012 240 mg TID)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, TID for up to 8 years. Subjects who had received BG00012 240 mg TID in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg BID (Prior BG00012 Matched Placebo)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, BID and 2 matching placebo capsules QD for up to 8 years. Subjects who had received placebo matched to BG00012 in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg TID (Prior BG00012 Matched Placebo)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, TID for up to 8 years. Subjects who had received placebo matched to BG00012 in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg BID (Prior Glatiramer Acetate [GA])
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, BID and 2 matching placebo capsules QD for up to 8 years. Subjects who had received Glatiramer Acetate (GA) in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, TID for up to 8 years. Subjects who had received GA in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg BID (Prior BG00012 240 mg BID)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, BID and 2 matching placebo capsules QD for up to 8 years. Subjects who had received BG00012 240 mg BID in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg TID (Prior BG00012 240 mg TID)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, TID for up to 8 years. Subjects who had received BG00012 240 mg TID in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg BID (Prior BG00012 Matched Placebo)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, BID and 2 matching placebo capsules QD for up to 8 years. Subjects who had received placebo matched to BG00012 in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg TID (Prior BG00012 Matched Placebo)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, TID for up to 8 years. Subjects who had received placebo matched to BG00012 in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg BID (Prior Glatiramer Acetate [GA])
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, BID and 2 matching placebo capsules QD for up to 8 years. Subjects who had received Glatiramer Acetate (GA) in the previous studies were included in this arm group.

    Subject analysis set title
    BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received BG00012 240 mg, 2 capsules (120 mg each) orally, TID for up to 8 years. Subjects who had received GA in the previous studies were included in this arm group.

    Primary: Number of Subjects with Treatment-Emergent Adverse Events (AEs)

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    End point title
    		 Number of Subjects with Treatment-Emergent Adverse Events (AEs) [1]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Safety population included all subjects who had any post-baseline safety follow-up in study 2008-004753-14, defined as any treatment emergent AE in study 2008-004753-14 or any post-baseline laboratory, vital signs, or physical exam assessment in study 2008-004753-14, and received at least one dose of study treatment in study 2008-004753-14.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 561
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be performed.
    End point values
    		 BG00012 240 mg BID BG00012 240 mg TID
    Number of subjects analysed
    868
    868
    Units: subjects
    824
    814
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Had Relapses

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    End point title
    		 Percentage of Subjects Who Had Relapses
    End point description
    Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: percentage of subjects
    40
    41
    34
    36
    31
    31
    No statistical analyses for this end point

    Secondary: Annualized Relapse Rate (ARR)

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    End point title
    		 Annualized Relapse Rate (ARR)
    End point description
    The annualized relapse rate is calculated as the total number of relapses occurred during the period for all subjects, divided by the total number of subject-years followed in the period. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: relapses per subject-years
        number (not applicable)
    0.159
    0.179
    0.200
    0.199
    0.184
    0.212
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Expanded Disability Status Scale (EDSS) at Week 384

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    End point title
    		 Change from Baseline in the Expanded Disability Status Scale (EDSS) at Week 384
    End point description
    The EDSS scale ranges from 0 (Normal neurological exam, no disability) to 10 (Death) in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist. Progression of disability was defined as at least a 1.0 point increase on the EDSS from a baseline EDSS >=1.0 that was sustained for at least 24 weeks, or a 1.5 point increase on the EDSS from a baseline EDSS =0 that was sustained for at least 24 weeks. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n =499, 502, 249, 248, 118, 118)
    2.44 ( 1.251 )
    2.43 ( 1.144 )
    2.50 ( 1.135 )
    2.54 ( 1.218 )
    2.57 ( 1.249 )
    2.68 ( 1.231 )
        Change at Week 384 (n =226, 219, 90, 98, 42, 50)
    0.28 ( 1.160 )
    0.26 ( 1.213 )
    0.37 ( 1.328 )
    0.53 ( 1.278 )
    0.39 ( 1.217 )
    0.49 ( 1.319 )
    No statistical analyses for this end point

    Secondary: Number of Gadolinium (Gd)-Enhancing Lesions as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Number of Gadolinium (Gd)-Enhancing Lesions as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    The Gd-enhancing lesions were evaluated using MRI technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: lesions
    arithmetic mean (standard deviation)
        Week 48 (n =191, 195, 83, 78, 41, 48)
    0.4 ( 1.87 )
    0.4 ( 1.29 )
    0.2 ( 0.66 )
    0.3 ( 1.14 )
    0.5 ( 1.19 )
    0.4 ( 1.14 )
        Week 96 (n =183, 186, 77, 75, 39, 46)
    0.4 ( 1.77 )
    0.4 ( 1.28 )
    0.1 ( 0.38 )
    0.2 ( 0.82 )
    0.6 ( 1.33 )
    0.3 ( 0.73 )
        Week 144 (n =156, 159, 66, 60, 32, 41)
    0.3 ( 1.66 )
    0.4 ( 1.30 )
    0.2 ( 0.44 )
    0.1 ( 0.29 )
    0.5 ( 2.48 )
    0.3 ( 1.59 )
        Week 192 (n =144, 149, 59, 55, 33, 38)
    0.4 ( 2.02 )
    0.5 ( 1.85 )
    0.5 ( 1.72 )
    0.3 ( 0.96 )
    0.2 ( 0.60 )
    0.6 ( 2.01 )
        Week 240 (n =135, 134, 55, 53, 29, 34)
    0.5 ( 3.14 )
    0.5 ( 2.29 )
    0.2 ( 0.50 )
    0.2 ( 0.51 )
    0.2 ( 0.58 )
    0.3 ( 0.75 )
        Week 288 (n =89, 97, 30, 31, 6, 16)
    0.2 ( 0.74 )
    0.5 ( 1.81 )
    0.1 ( 0.40 )
    0.7 ( 2.76 )
    0.0 ( 0.00 )
    0.3 ( 0.77 )
    No statistical analyses for this end point

    Secondary: Volume of Gd-Enhancing Lesions as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Volume of Gd-Enhancing Lesions as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    The Gd-enhancing lesions were evaluated using MRI technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, ‘n’ signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: millimetre cube (mm^3)
    arithmetic mean (standard deviation)
        Baseline (n =209, 220, 104, 99, 47, 60)
    31.7 ( 179.28 )
    48.6 ( 205.43 )
    96.0 ( 260.79 )
    142.5 ( 459.76 )
    37.1 ( 138.82 )
    41.7 ( 116.55 )
        Week 48 (n =190, 197, 83, 77, 40, 48)
    59.6 ( 526.51 )
    70.0 ( 366.63 )
    18.8 ( 91.47 )
    25.3 ( 108.19 )
    42.5 ( 123.67 )
    42.7 ( 148.11 )
        Week 96 (n =182, 185, 77, 73, 38, 46)
    49.1 ( 245.14 )
    56.1 ( 271.29 )
    27.7 ( 204.80 )
    13.3 ( 67.01 )
    64.3 ( 183.16 )
    22.3 ( 60.83 )
        Week 144 (n =155, 160, 66, 59, 31, 41)
    44.1 ( 291.14 )
    47.0 ( 169.68 )
    18.8 ( 66.15 )
    3.8 ( 25.03 )
    42.6 ( 142.55 )
    92.9 ( 397.69 )
        Week 192 (n =143, 148, 59, 54, 32, 38)
    39.1 ( 217.89 )
    54.5 ( 251.31 )
    45.8 ( 156.88 )
    19.9 ( 79.19 )
    12.0 ( 40.56 )
    55.1 ( 169.16 )
        Week 240 (n =134, 133, 55, 52, 28, 34)
    96.8 ( 650.06 )
    69.3 ( 374.67 )
    21.7 ( 77.87 )
    14.1 ( 45.22 )
    17.5 ( 46.19 )
    17.1 ( 48.41 )
        Week 288 (n =89, 97, 30, 31, 6, 16)
    18.2 ( 93.28 )
    53.1 ( 250.87 )
    7.9 ( 30.09 )
    230.2 ( 1092.11 )
    0.0 ( 0.00 )
    34.1 ( 102.87 )
    No statistical analyses for this end point

    Secondary: Number of New or Newly Enlarging T2 Lesions as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Number of New or Newly Enlarging T2 Lesions as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    The T2 lesions were evaluated using MRI technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: lesions
    arithmetic mean (standard deviation)
        Week 48 (n =198, 201, 84, 81, 42, 50)
    1.6 ( 4.07 )
    2.2 ( 6.15 )
    2.7 ( 4.96 )
    2.4 ( 5.45 )
    3.4 ( 6.57 )
    2.1 ( 3.83 )
        Week 96 (n =191, 192, 78, 77, 40, 47)
    3.4 ( 8.35 )
    4.1 ( 10.01 )
    3.8 ( 7.24 )
    2.9 ( 6.78 )
    4.9 ( 8.51 )
    3.4 ( 5.13 )
        Week 144 (n =163, 168, 67, 63, 35, 44)
    4.2 ( 9.81 )
    5.2 ( 10.01 )
    4.0 ( 7.27 )
    4.3 ( 10.12 )
    5.7 ( 9.45 )
    5.2 ( 9.68 )
        Week 192 (n =151, 155, 61, 56, 33, 40)
    5.8 ( 14.04 )
    7.5 ( 15.14 )
    5.6 ( 10.09 )
    5.6 ( 14.19 )
    5.5 ( 9.94 )
    5.6 ( 13.35 )
        Week 240 (n =139, 142, 55, 55, 30, 37)
    7.4 ( 17.09 )
    9.5 ( 20.33 )
    8.2 ( 14.87 )
    7.7 ( 17.89 )
    6.8 ( 11.74 )
    7.5 ( 16.76 )
        Week 288 (n =123, 123, 45, 49, 26, 32)
    8.2 ( 18.53 )
    12.4 ( 28.23 )
    7.5 ( 13.89 )
    10.4 ( 22.05 )
    8.9 ( 15.04 )
    6.0 ( 8.90 )
    No statistical analyses for this end point

    Secondary: Volume of New or Newly Enlarging T2 Lesions as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Volume of New or Newly Enlarging T2 Lesions as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    The T2 lesions were evaluated using MRI technique.MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, ‘n’ signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: mm^3
    arithmetic mean (standard deviation)
        Baseline (n =209, 220, 104, 99, 47, 60)
    10231.9 ( 11214.17 )
    10408.3 ( 12166.80 )
    8883.7 ( 8570.10 )
    10806.3 ( 12060.05 )
    12628.9 ( 11258.69 )
    13044.4 ( 14608.50 )
        Week 48 (n =194, 199, 84, 78, 40, 50)
    9951.9 ( 10750.15 )
    9849.6 ( 10986.36 )
    8992.1 ( 7952.13 )
    10114.5 ( 10121.61 )
    11160.7 ( 9565.55 )
    12979.0 ( 14415.86 )
        Week 96 (n =187, 190, 78, 74, 38, 47)
    10331.3 ( 11359.81 )
    10434.0 ( 12201.38 )
    8645.2 ( 7787.60 )
    9985.7 ( 10715.73 )
    11318.1 ( 9873.73 )
    13974.1 ( 15432.10 )
        Week 144 (n =162, 167, 67, 61, 34, 44)
    9930.1 ( 10686.26 )
    10280.7 ( 11324.58 )
    8829.4 ( 7482.93 )
    9792.3 ( 9842.28 )
    10188.5 ( 8064.09 )
    12949.7 ( 14036.15 )
        Week 192 (n =149, 154, 61, 55, 32, 40)
    9837.7 ( 10845.04 )
    10760.0 ( 11987.16 )
    9077.6 ( 7794.52 )
    10576.3 ( 12029.26 )
    10421.9 ( 8773.41 )
    11671.5 ( 13124.47 )
        Week 240 (n =138, 141, 55, 54, 29, 37)
    10611.2 ( 11633.95 )
    11087.5 ( 12464.90 )
    9711.1 ( 8709.46 )
    10591.4 ( 11613.26 )
    11009.9 ( 9551.94 )
    12254.4 ( 13732.10 )
        Week 288 (n =121, 122, 45, 49, 26, 32)
    9611.8 ( 9447.18 )
    9800.8 ( 11279.84 )
    8819.8 ( 8866.90 )
    10537.6 ( 10684.47 )
    11586.3 ( 9728.19 )
    10404.8 ( 12245.75 )
    No statistical analyses for this end point

    Secondary: Number of T1 Hypointense Lesions as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Number of T1 Hypointense Lesions as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    The T1 hypointense lesions were evaluated using MRI technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: lesions
    arithmetic mean (standard deviation)
        Week 48 (n =183, 184, 79, 76, 41, 48)
    0.8 ( 2.13 )
    1.0 ( 2.37 )
    1.8 ( 3.81 )
    1.7 ( 3.71 )
    2.0 ( 4.22 )
    1.3 ( 2.64 )
        Week 96 (n =171, 178, 75, 72, 39, 45)
    1.7 ( 3.63 )
    1.9 ( 3.91 )
    1.8 ( 3.33 )
    2.1 ( 5.00 )
    3.0 ( 5.85 )
    1.9 ( 3.44 )
        Week 144 (n =148, 155, 63, 53, 32, 41)
    2.0 ( 4.61 )
    2.8 ( 5.19 )
    2.0 ( 3.69 )
    2.6 ( 7.02 )
    3.1 ( 6.20 )
    2.9 ( 5.19 )
        Week 192 (n =141, 145, 58, 53, 33, 38)
    2.9 ( 7.03 )
    3.4 ( 6.79 )
    2.9 ( 5.12 )
    3.8 ( 10.71 )
    3.3 ( 6.74 )
    3.0 ( 7.14 )
        Week 240 (n =134, 136, 55, 53, 29, 34)
    3.4 ( 8.25 )
    4.8 ( 9.39 )
    4.0 ( 7.52 )
    4.9 ( 13.30 )
    4.0 ( 8.06 )
    4.2 ( 10.20 )
        Week 288 (n =88, 94, 30, 32, 6, 16)
    2.7 ( 5.72 )
    5.9 ( 12.02 )
    4.5 ( 7.38 )
    3.6 ( 4.51 )
    1.0 ( 1.10 )
    5.6 ( 6.81 )
    No statistical analyses for this end point

    Secondary: Volume of T1 Hypointense Lesions as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Volume of T1 Hypointense Lesions as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    The T1 hypointense lesions were evaluated using MRI technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, ‘n’ signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: mm^3
    arithmetic mean (standard deviation)
        Baseline (n =209, 220, 104, 99, 47, 60)
    3640.1 ( 5598.31 )
    3447.3 ( 4900.96 )
    2754.2 ( 3552.30 )
    3623.1 ( 5549.13 )
    3204.3 ( 4221.55 )
    3572.6 ( 4915.24 )
        Week 48 (n =190, 197, 83, 77, 40, 48)
    3829.5 ( 5824.26 )
    3715.5 ( 5112.21 )
    2891.9 ( 3034.00 )
    3936.0 ( 5271.89 )
    3271.0 ( 4157.24 )
    3743.3 ( 5374.24 )
        Week 96 (n =183, 186, 77, 73, 38, 46)
    3841.2 ( 5682.74 )
    3853.7 ( 5428.66 )
    2921.0 ( 3327.93 )
    3849.4 ( 5167.13 )
    3510.4 ( 4672.80 )
    3949.7 ( 5018.63 )
        Week 144 (n =157, 164, 67, 58, 33, 42)
    3767.4 ( 4969.23 )
    4074.0 ( 5413.85 )
    3145.6 ( 3366.27 )
    4006.9 ( 5062.08 )
    3499.2 ( 4198.50 )
    4126.1 ( 5695.44 )
        Week 192 (n =145, 149, 60, 54, 32, 38)
    3834.9 ( 4942.19 )
    4177.4 ( 5301.68 )
    3385.4 ( 3575.44 )
    4330.0 ( 5136.67 )
    3592.0 ( 4069.39 )
    4089.3 ( 4996.13 )
        Week 240 (n =135, 137, 55, 52, 28, 34)
    4038.6 ( 5145.85 )
    4238.2 ( 5248.84 )
    3406.4 ( 3936.73 )
    3823.9 ( 4274.82 )
    3503.4 ( 3933.75 )
    4057.7 ( 5223.62 )
        Week 288 (n =113, 121, 40, 45, 20, 29)
    3603.3 ( 4394.60 )
    3973.1 ( 5202.05 )
    3350.6 ( 4140.34 )
    4187.5 ( 4835.43 )
    3264.9 ( 3639.91 )
    2959.1 ( 3918.62 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Brain Atrophy

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    End point title
    		 Percent Change from Baseline in Brain Atrophy
    End point description
    Brain atrophy was measured using magnetic resonance imaging (MRI) technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, ‘n’ signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Week 48 (n =162, 162, 56, 64, 33, 42)
    -1.206 ( 1.1006 )
    -1.263 ( 1.0848 )
    -1.487 ( 1.3086 )
    -1.320 ( 1.4021 )
    -1.496 ( 1.1316 )
    -1.414 ( 1.1882 )
        Change at Week 96 (n =144, 145, 50, 56, 30, 37)
    -1.372 ( 1.1382 )
    -1.500 ( 1.0893 )
    -1.589 ( 1.3630 )
    -1.775 ( 1.7191 )
    -1.883 ( 1.2383 )
    -1.810 ( 1.4556 )
        Change at Week 144 (n =122, 133, 44, 49, 28, 36)
    -1.708 ( 1.4109 )
    -1.876 ( 1.2604 )
    -2.139 ( 1.5884 )
    -2.353 ( 1.7897 )
    -2.386 ( 1.3168 )
    -2.252 ( 2.2124 )
        Change at Week 192 (n =114, 120, 41, 45, 29, 36)
    -2.138 ( 1.6831 )
    -2.117 ( 1.4000 )
    -2.230 ( 1.7755 )
    -2.476 ( 1.7062 )
    -2.645 ( 1.2284 )
    -2.417 ( 2.0486 )
        Change at Week 240 (n =92, 95, 37, 40, 18, 26)
    -2.313 ( 1.6309 )
    -2.253 ( 1.3721 )
    -2.271 ( 1.4817 )
    -2.593 ( 1.9043 )
    -2.249 ( 1.2985 )
    -2.790 ( 2.2188 )
        Change at Week 288 (n =71, 72, 25, 30, 15, 23)
    -2.216 ( 1.5744 )
    -2.271 ( 1.2193 )
    -2.470 ( 1.6757 )
    -2.849 ( 1.9648 )
    -2.657 ( 1.7051 )
    -2.496 ( 1.3699 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Magnetization Transfer Ratio (MTR)

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    End point title
    		 Percent Change from Baseline in Magnetization Transfer Ratio (MTR)
    End point description
    Magnetization Transfer Ratio (MTR) was measured using MRI technique. MRI cohort included subjects in the study 2008-004753-14 ITT population who had consented to participate in the MRI sub-study and have any MRI data in Studies 2006-003696-12,2006-003697-10or 2008-004753-14. Here, ‘n’ signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per the treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 288
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    213
    222
    105
    103
    49
    60
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Week 48 (n =126, 118, 49, 56, 20, 23)
    -0.325 ( 5.4932 )
    -0.383 ( 4.8621 )
    1.034 ( 7.3548 )
    -0.567 ( 4.4766 )
    -0.081 ( 13.6416 )
    -0.334 ( 1.5103 )
        Change at Week 96 (n =118, 113, 46, 50, 20, 20)
    -0.427 ( 6.6493 )
    -0.532 ( 4.9880 )
    1.630 ( 7.6584 )
    -0.947 ( 7.0771 )
    -4.269 ( 12.6065 )
    0.215 ( 1.4270 )
        Change at Week 144 (n =103, 107, 45, 37, 19, 24)
    -0.042 ( 9.2548 )
    0.509 ( 7.2692 )
    1.525 ( 8.6421 )
    1.411 ( 12.2825 )
    -4.460 ( 10.3887 )
    3.119 ( 8.1676 )
        Change at Week 192 (n =100, 100, 42, 41, 25, 23)
    1.038 ( 10.8680 )
    0.955 ( 8.6105 )
    3.012 ( 9.3831 )
    3.103 ( 13.0046 )
    1.384 ( 15.7611 )
    3.841 ( 10.8600 )
        Change at Week 240 (n =91, 90, 40, 42, 23, 20)
    -0.002 ( 15.6190 )
    1.647 ( 8.3094 )
    3.213 ( 9.6621 )
    4.108 ( 13.8103 )
    2.959 ( 16.8386 )
    0.673 ( 25.9962 )
        Change at Week 288 (n =65, 71, 19, 25, 5, 14)
    0.002 ( 4.0206 )
    -0.391 ( 4.6415 )
    -0.666 ( 2.0741 )
    -0.622 ( 2.2922 )
    -0.466 ( 0.9410 )
    -1.114 ( 2.4539 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form-36 Health Survey (SF-36®) at Week 384

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    End point title
    		 Change From Baseline in Short Form-36 Health Survey (SF-36®) at Week 384
    End point description
    The SF-36 is a brief (36-item) scale reflecting the impact of both dysfunctions and general health perception the questionnaire measures: 1.physical function (PF),2. role physical (RF),3. bodily pain (BP),4. role emotional (RE),5. social function (SF), 6. general health (GH),7. vitality (VT), 8. mental health (MH). Items 1-4 primarily contribute to the PCS score of the SF-36. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. The questions related to each dimension are scored on a scale from 0 (worst score) to 100 (best score), with higher scores indicating better function. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline: PF (n=494,487,244,240,115,112)
    68.48 ( 25.938 )
    71.78 ( 24.849 )
    69.67 ( 24.481 )
    67.97 ( 26.279 )
    69.10 ( 25.226 )
    68.20 ( 25.370 )
        Change at Week 384: PF (n=236,215,90,97,43,48)
    0.73 ( 21.972 )
    -4.79 ( 24.641 )
    -7.37 ( 22.253 )
    -6.89 ( 23.194 )
    -6.19 ( 21.719 )
    -6.25 ( 28.350 )
        Baseline: RF (n =494,486,244,238,114,112)
    56.46 ( 41.254 )
    58.42 ( 41.280 )
    56.35 ( 40.896 )
    59.87 ( 41.747 )
    55.26 ( 40.390 )
    53.57 ( 42.029 )
        Change at Week 384: RF (n=232,215,90,94,43,48)
    3.20 ( 48.259 )
    -2.75 ( 47.283 )
    -10.00 ( 43.188 )
    -8.24 ( 53.177 )
    -12.21 ( 40.595 )
    -1.04 ( 54.568 )
        Baseline: BP (n =494,490,244,240,115,112)
    69.68 ( 25.587 )
    70.42 ( 24.688 )
    68.51 ( 26.163 )
    69.44 ( 26.016 )
    69.30 ( 25.766 )
    68.59 ( 26.102 )
        Change at Week 384: BP (n=237,216,90,97,43,48)
    1.32 ( 28.525 )
    -1.47 ( 25.779 )
    -2.92 ( 23.486 )
    -4.36 ( 25.935 )
    -3.60 ( 22.138 )
    -4.46 ( 33.297 )
        Baseline: GH (n =493,489,240,238,115,110)
    53.99 ( 21.563 )
    55.44 ( 20.768 )
    54.45 ( 18.690 )
    52.42 ( 20.028 )
    51.21 ( 18.707 )
    52.58 ( 19.675 )
        Change at Week 384: GH (n=234,213,86,95,42,47)
    0.87 ( 18.744 )
    -2.12 ( 20.595 )
    -2.28 ( 16.752 )
    -0.52 ( 22.035 )
    -5.64 ( 18.270 )
    1.21 ( 21.674 )
        Baseline: VT (n =492,486,242,239,115,111)
    50.48 ( 20.966 )
    52.21 ( 19.842 )
    50.63 ( 19.130 )
    50.64 ( 21.069 )
    51.30 ( 19.703 )
    50.33 ( 20.019 )
        Change at Week 384: VT (n=235,214,87,96,41,47)
    1.11 ( 19.857 )
    -0.73 ( 19.033 )
    -4.67 ( 17.934 )
    0.40 ( 20.822 )
    -6.71 ( 20.236 )
    1.03 ( 19.829 )
        Baseline: SF (n =494,490,244,239,115,112)
    71.46 ( 24.451 )
    71.53 ( 24.394 )
    69.67 ( 24.581 )
    72.23 ( 24.699 )
    69.02 ( 24.688 )
    69.53 ( 25.100 )
        Change at Week 384: SF (n=237,216,90,96,43,48)
    -2.16 ( 25.575 )
    -3.30 ( 24.912 )
    -5.69 ( 22.184 )
    -2.08 ( 27.724 )
    -10.76 ( 34.350 )
    -0.52 ( 25.780 )
        Baseline: RE (n =491,485,241,238,115,111)
    64.87 ( 40.653 )
    65.57 ( 40.015 )
    62.86 ( 42.715 )
    62.61 ( 41.280 )
    60.29 ( 41.393 )
    64.26 ( 41.854 )
        Change at Week 384: RE (n=233,214,90,96,43,47)
    0.43 ( 49.950 )
    0.47 ( 43.513 )
    -12.22 ( 42.532 )
    4.17 ( 44.656 )
    -13.18 ( 42.501 )
    -3.55 ( 48.769 )
        Baseline: MH (n =492,486,242,239,115,111)
    65.01 ( 19.818 )
    66.24 ( 19.060 )
    65.42 ( 17.658 )
    65.15 ( 19.233 )
    62.30 ( 17.347 )
    63.61 ( 18.414 )
        Change at Week 384: MH (n=235,214,87,96,41,47)
    1.32 ( 19.715 )
    2.31 ( 18.095 )
    -3.91 ( 19.897 )
    2.33 ( 17.524 )
    -0.29 ( 21.989 )
    -2.06 ( 20.066 )
        Baseline:MCS(n=488,480,237,235,114,108)
    45.40 ( 11.130 )
    45.63 ( 10.272 )
    45.13 ( 10.932 )
    45.31 ( 10.907 )
    44.00 ( 10.702 )
    45.03 ( 10.642 )
        Change at Week 384:MCS(n=226,211,85,92,41,45)
    0.05 ( 12.415 )
    0.87 ( 10.028 )
    -2.55 ( 10.328 )
    1.97 ( 10.657 )
    -2.59 ( 12.895 )
    0.08 ( 10.328 )
        Baseline:PCS(n=488,480,237,235,114,108)
    43.53 ( 9.884 )
    44.44 ( 10.048 )
    43.74 ( 9.739 )
    43.56 ( 10.267 )
    43.68 ( 10.359 )
    43.15 ( 10.091 )
        Change at Week 384:PCS (n=226,211,85,92,41,45)
    0.55 ( 9.373 )
    -1.94 ( 10.532 )
    -2.29 ( 8.929 )
    -3.25 ( 9.998 )
    -2.70 ( 8.860 )
    -1.59 ( 10.765 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol 5 Dimensions Questionnaire (EQ-5D) Health Survey - EQ-5D Index Score at Week 384

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    End point title
    		 Change From Baseline in EuroQol 5 Dimensions Questionnaire (EQ-5D) Health Survey - EQ-5D Index Score at Week 384
    End point description
    The EQ-5D is a generic health-related quality of life instrument consisting of 2 components, EQ-5D index score and EQ-VAS. The EQ-5D provides a profile of the subject's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject is instructed to indicate whether he or she has (1) "no problems", (2) "some problems", or (3) "severe problems". A positive change from baseline indicates improvement. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n =488, 484, 239, 239, 115, 112)
    0.73 ( 0.210 )
    0.73 ( 0.222 )
    0.72 ( 0.223 )
    0.71 ( 0.244 )
    0.71 ( 0.246 )
    0.72 ( 0.189 )
        Change at Week 384 (n =230, 212, 86, 96, 42, 48)
    0.01 ( 0.251 )
    0.00 ( 0.233 )
    -0.07 ( 0.269 )
    0.00 ( 0.249 )
    -0.04 ( 0.253 )
    -0.03 ( 0.241 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol 5 Dimensions Questionnaire (EQ-5D) Health Survey - Visual Analog Scale (VAS) at Week 384

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    End point title
    		 Change From Baseline in EuroQol 5 Dimensions Questionnaire (EQ-5D) Health Survey - Visual Analog Scale (VAS) at Week 384
    End point description
    The EQ-5D is a generic health-related quality of life instrument consisting of 2 components, EQ-5D index score and EQ-VAS. In EQ-VAS subjects are asked to rate their current health on a 20 centimetre (cm) scale from 0 to 100 where 0 represents “worst imaginable health state” and 100 represents “best imaginable health state". A positive change from baseline indicates improvement. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n =492, 488, 243, 238, 113, 112)
    70.97 ( 18.460 )
    70.48 ( 19.993 )
    70.40 ( 17.630 )
    69.44 ( 19.907 )
    66.80 ( 18.846 )
    69.07 ( 20.094 )
        Change at Week 384 (n =235, 215, 91, 95, 42, 48)
    -0.48 ( 19.631 )
    -1.67 ( 18.855 )
    -7.24 ( 18.419 )
    -3.17 ( 22.003 )
    -1.71 ( 25.330 )
    -4.11 ( 16.270 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Visual Function Test Scores at Week 384

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    End point title
    		 Change From Baseline in Visual Function Test Scores at Week 384
    End point description
    Subjects were tested using the contrast level of 100%, 2.5%, and 1.25% charts, and the scores were defined as the number of letters identified correctly for each chart (the maximum score was 60). Higher scores indicate better functioning. A positive change from baseline indicates better functioning. ITT population included subjects who had entered study 2008-004753-14 and received at least one dose of study treatment. Here, 'n' signifies number of subjects analysed at specific timepoint. Data for this endpoint was summarised as per treatment received in previous studies (2006-003696-12 and 2006-003697-10).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 384
    End point values
    		 BG00012 240 mg BID (Prior BG00012 240 mg BID) BG00012 240 mg TID (Prior BG00012 240 mg TID) BG00012 240 mg BID (Prior BG00012 Matched Placebo) BG00012 240 mg TID (Prior BG00012 Matched Placebo) BG00012 240 mg BID (Prior Glatiramer Acetate [GA]) BG00012 240 mg TID (Prior Glatiramer Acetate [GA])
    Number of subjects analysed
    501
    502
    249
    248
    118
    118
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline:100%Chart (n=501,502,249,248,118,118)
    54.7 ( 7.95 )
    55.0 ( 7.84 )
    55.1 ( 7.26 )
    54.8 ( 7.12 )
    54.3 ( 8.26 )
    55.0 ( 6.73 )
        Change at Week384:100%Chart(n=231,216,87,99,42,50)
    -0.4 ( 6.76 )
    -1.9 ( 6.81 )
    -1.4 ( 8.48 )
    -1.2 ( 7.53 )
    -1.6 ( 8.05 )
    -0.7 ( 5.17 )
        Baseline:2.5%Chart(n=501,502,249,248,118,118)
    32.4 ( 12.17 )
    32.6 ( 11.76 )
    32.4 ( 11.42 )
    32.3 ( 11.99 )
    31.8 ( 12.36 )
    31.7 ( 12.41 )
        Change at Week384:2.5%Chart(n=231,216,87,99,42,50)
    -2.4 ( 10.77 )
    -3.3 ( 10.43 )
    -1.5 ( 11.77 )
    -4.9 ( 11.14 )
    -4.0 ( 11.90 )
    -2.1 ( 9.86 )
        Baseline:1.25%Chart(n=501,502,249,248,118,118)
    24.1 ( 12.45 )
    24.2 ( 12.28 )
    23.8 ( 12.11 )
    23.7 ( 12.96 )
    23.4 ( 11.76 )
    22.2 ( 13.25 )
        Change atWeek384:1.25%Chart(n=231,216,87,99,42,50)
    -5.8 ( 13.39 )
    -6.0 ( 11.77 )
    -4.1 ( 13.04 )
    -7.4 ( 12.42 )
    -6.7 ( 13.78 )
    -5.0 ( 12.74 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of the study up to follow-up (Day 1 up to Week 561)
    Adverse event reporting additional description
    Safety population included all subjects who had any post-baseline safety follow-up in study 2008-004753-14, defined as any treatment emergent AE in study 2008-004753-14 or any post-baseline laboratory, vital signs, or physical exam assessment in study 2008-004753-14, and received at least one dose of study treatment in study 2008-004753-14.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    BG00012 240 mg BID
    Reporting group description
    		 Subjects received BG00012 240 mg (120 mg each) capsules orally, BID and 2 matching placebo capsules QD up to 8 years.

    Reporting group title
    BG00012 240 mg TID
    Reporting group description
    		 Subjects received BG00012 240 mg (120 mg each) capsules orally, TID up to 8 years.

    Serious adverse events
    		 BG00012 240 mg BID BG00012 240 mg TID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    279 / 868 (32.14%)
    272 / 868 (31.34%)
         number of deaths (all causes)
    5
    6
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenolymphoma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 868 (0.35%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign ovarian tumour
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowenoid papulosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    4 / 868 (0.46%)
    8 / 868 (0.92%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer stage II
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid tumour of the pancreas
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix neoplasm
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage II
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage unspecified
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 868 (0.23%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma malignant
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal neoplasm benign
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    3 / 868 (0.35%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland cancer
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous endometrial carcinoma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    6 / 868 (0.69%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominoplasty
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve replacement
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicectomy
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neck suspension
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bunion operation
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Caesarean section
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel decompression
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cochlea implant
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele repair
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female sterilisation
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mammoplasty
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device change
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device removal
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cystectomy
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative care
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroidectomy
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia repair
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein operation
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication of pregnancy
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Capsular contracture associated with breast implant
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 868 (0.00%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 868 (0.35%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Treatment failure
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast necrosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 868 (0.00%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrocystic breast disease
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 868 (0.12%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 868 (0.12%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic adhesions
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranasal cyst
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia nervosa
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burnout syndrome
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catatonia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 868 (0.00%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Morbid thoughts
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic behaviour
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder due to a general medical condition
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 868 (0.35%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 868 (0.23%)
    7 / 868 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accident at work
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 868 (0.23%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    3 / 868 (0.35%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug toxicity
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    13 / 868 (1.50%)
    18 / 868 (2.07%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 868 (0.35%)
    4 / 868 (0.46%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 868 (0.35%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    4 / 868 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint sprain
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 868 (0.12%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    3 / 868 (0.35%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    4 / 868 (0.46%)
    5 / 868 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 868 (0.12%)
    5 / 868 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cytogenetic abnormality
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb malformation
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve prolapse
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 868 (0.12%)
    5 / 868 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wolff-parkinson-white syndrome
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    3 / 868 (0.35%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    4 / 868 (0.46%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    116 / 868 (13.36%)
    122 / 868 (14.06%)
         occurrences causally related to treatment / all
    3 / 229
    9 / 217
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 868 (0.12%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing-remitting multiple sclerosis
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 868 (0.12%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal ischaemia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 868 (0.23%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal mucosal disorder
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 868 (0.12%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 868 (0.12%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurogenic bladder
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basedow's disease
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    4 / 868 (0.46%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    2 / 868 (0.23%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    5 / 868 (0.58%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    5 / 868 (0.58%)
    4 / 868 (0.46%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    1 / 868 (0.12%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal deformity
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 868 (0.23%)
    4 / 868 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteriuria
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 868 (0.23%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 868 (0.00%)
    2 / 868 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 868 (0.12%)
    3 / 868 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloma viral infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 868 (0.69%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculoma
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyothorax
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrub typhus
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 868 (0.23%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    10 / 868 (1.15%)
    4 / 868 (0.46%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    1 / 868 (0.12%)
    0 / 868 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy (PML)
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 868 (0.12%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 868 (0.00%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    2 / 868 (0.23%)
    1 / 868 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BG00012 240 mg BID BG00012 240 mg TID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    779 / 868 (89.75%)
    767 / 868 (88.36%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    170 / 868 (19.59%)
    165 / 868 (19.01%)
         occurrences all number
    264
    227
    Hot flush
         subjects affected / exposed
    44 / 868 (5.07%)
    53 / 868 (6.11%)
         occurrences all number
    62
    71
    Hypertension
         subjects affected / exposed
    51 / 868 (5.88%)
    43 / 868 (4.95%)
         occurrences all number
    60
    46
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    100 / 868 (11.52%)
    102 / 868 (11.75%)
         occurrences all number
    126
    139
    Pyrexia
         subjects affected / exposed
    47 / 868 (5.41%)
    43 / 868 (4.95%)
         occurrences all number
    62
    55
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    54 / 868 (6.22%)
    66 / 868 (7.60%)
         occurrences all number
    71
    82
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    31 / 868 (3.57%)
    46 / 868 (5.30%)
         occurrences all number
    37
    54
    Depression
         subjects affected / exposed
    102 / 868 (11.75%)
    87 / 868 (10.02%)
         occurrences all number
    125
    114
    Insomnia
         subjects affected / exposed
    52 / 868 (5.99%)
    51 / 868 (5.88%)
         occurrences all number
    59
    59
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    53 / 868 (6.11%)
    59 / 868 (6.80%)
         occurrences all number
    74
    80
    Albumin urine present
         subjects affected / exposed
    66 / 868 (7.60%)
    62 / 868 (7.14%)
         occurrences all number
    107
    86
    Lymphocyte count decreased
         subjects affected / exposed
    56 / 868 (6.45%)
    42 / 868 (4.84%)
         occurrences all number
    85
    71
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    60 / 868 (6.91%)
    63 / 868 (7.26%)
         occurrences all number
    113
    108
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    60 / 868 (6.91%)
    45 / 868 (5.18%)
         occurrences all number
    86
    61
    Headache
         subjects affected / exposed
    145 / 868 (16.71%)
    131 / 868 (15.09%)
         occurrences all number
    247
    205
    Hypoaesthesia
         subjects affected / exposed
    64 / 868 (7.37%)
    49 / 868 (5.65%)
         occurrences all number
    86
    78
    Multiple sclerosis relapse
         subjects affected / exposed
    324 / 868 (37.33%)
    335 / 868 (38.59%)
         occurrences all number
    724
    769
    Paraesthesia
         subjects affected / exposed
    57 / 868 (6.57%)
    59 / 868 (6.80%)
         occurrences all number
    78
    72
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    52 / 868 (5.99%)
    42 / 868 (4.84%)
         occurrences all number
    83
    59
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    50 / 868 (5.76%)
    55 / 868 (6.34%)
         occurrences all number
    75
    67
    Abdominal pain upper
         subjects affected / exposed
    69 / 868 (7.95%)
    76 / 868 (8.76%)
         occurrences all number
    90
    108
    Diarrhoea
         subjects affected / exposed
    111 / 868 (12.79%)
    118 / 868 (13.59%)
         occurrences all number
    159
    162
    Nausea
         subjects affected / exposed
    56 / 868 (6.45%)
    61 / 868 (7.03%)
         occurrences all number
    71
    77
    Vomiting
         subjects affected / exposed
    42 / 868 (4.84%)
    45 / 868 (5.18%)
         occurrences all number
    52
    54
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    47 / 868 (5.41%)
    32 / 868 (3.69%)
         occurrences all number
    57
    36
    Pruritus
         subjects affected / exposed
    50 / 868 (5.76%)
    38 / 868 (4.38%)
         occurrences all number
    61
    50
    Rash
         subjects affected / exposed
    45 / 868 (5.18%)
    40 / 868 (4.61%)
         occurrences all number
    68
    53
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    49 / 868 (5.65%)
    61 / 868 (7.03%)
         occurrences all number
    71
    90
    Microalbuminuria
         subjects affected / exposed
    55 / 868 (6.34%)
    61 / 868 (7.03%)
         occurrences all number
    78
    103
    Proteinuria
         subjects affected / exposed
    76 / 868 (8.76%)
    81 / 868 (9.33%)
         occurrences all number
    108
    127
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    97 / 868 (11.18%)
    115 / 868 (13.25%)
         occurrences all number
    146
    169
    Back pain
         subjects affected / exposed
    125 / 868 (14.40%)
    125 / 868 (14.40%)
         occurrences all number
    179
    170
    Muscle spasms
         subjects affected / exposed
    38 / 868 (4.38%)
    49 / 868 (5.65%)
         occurrences all number
    46
    78
    Musculoskeletal pain
         subjects affected / exposed
    35 / 868 (4.03%)
    49 / 868 (5.65%)
         occurrences all number
    42
    59
    Pain in extremity
         subjects affected / exposed
    102 / 868 (11.75%)
    92 / 868 (10.60%)
         occurrences all number
    157
    128
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    82 / 868 (9.45%)
    98 / 868 (11.29%)
         occurrences all number
    121
    150
    Gastroenteritis
         subjects affected / exposed
    52 / 868 (5.99%)
    33 / 868 (3.80%)
         occurrences all number
    65
    40
    Herpes zoster
         subjects affected / exposed
    47 / 868 (5.41%)
    38 / 868 (4.38%)
         occurrences all number
    51
    43
    Influenza
         subjects affected / exposed
    87 / 868 (10.02%)
    67 / 868 (7.72%)
         occurrences all number
    113
    87
    Nasopharyngitis
         subjects affected / exposed
    220 / 868 (25.35%)
    226 / 868 (26.04%)
         occurrences all number
    564
    528
    Pharyngitis
         subjects affected / exposed
    44 / 868 (5.07%)
    50 / 868 (5.76%)
         occurrences all number
    63
    62
    Sinusitis
         subjects affected / exposed
    65 / 868 (7.49%)
    63 / 868 (7.26%)
         occurrences all number
    107
    128
    Upper respiratory tract infection
         subjects affected / exposed
    143 / 868 (16.47%)
    136 / 868 (15.67%)
         occurrences all number
    296
    253
    Urinary tract infection
         subjects affected / exposed
    196 / 868 (22.58%)
    164 / 868 (18.89%)
         occurrences all number
    394
    319

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2010
    Extension of the duration of the study from 2 years to 5 years or marketing authorization (if approved), whichever occurs first.
    17 Mar 2014
    Extended the study duration for each subject from 5 years to 8 years and to change the dosing regimen from dose-blind dosing with BG00012 240 mg twice a day (BID) or three times a day (TID) to open-label dosing with BG00012 at a dose of 240 mg BID for all subjects.
    02 Sep 2014
    Updated the safety reporting information.
    16 Nov 2014
    Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of severe, prolonged lymphopenia following BG00012 administration. Severe, prolonged lymphopenia is a known risk factor for PML. In the controlled and uncontrolled BG00012 clinical studies, 2% of subjects experienced lymphocyte counts <0.5*10^9 per litre (/L) for at least six months. In these subjects, the majority of lymphocyte counts remained <0.5*10^9/L with continued therapy. The study protocol is being amended to enable the early identification of subjects who are at risk for developing severe, prolonged lymphopenia, and to provide additional guidance on the management of such subjects.
    21 Jan 2016
    - Extended the study duration by an additional 4 years to collect data on long-term efficacy and safety of BG00012. - Increased the minimal duration of follow-up for lymphopenic subjects upon discontinuation of treatment with BG00012, per Committee for Medicinal Products for Human Use (CHMP) recommendations.
    07 Nov 2016
    Removed the discontinuation criteria of elevated serum creatinine (either >1.2*baseline serum creatinine or >1.2*upper limit of normal [ULN]), positive urinalysis, and low white blood cell (WBC) count.
    05 Feb 2018
    Changed the length of the study from 12 years to 8 years.

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

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