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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of PEGylated Interferon Beta-1a (BIIB017) in Subjects With Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    2008-006333-27
    Trial protocol
    LV   EE   DE   BE   NL   ES   CZ   BG   GR   GB  
    Global end of trial date
    24 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Feb 2016
    First version publication date
    21 Feb 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    105MS301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00906399
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen Idec
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Idec Study Medical Director, Biogen Idec, Clinicaltrials@biogenidec.com
    Scientific contact
    Biogen Idec Study Medical Director, Biogen Idec, Clinicaltrials@biogenidec.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
    24 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine the efficacy of peginterferon beta-1a in reducing the annualized relapse rate (ARR) in subjects with relapsing multiple sclerosis (RMS) at 1 year. The secondary objectives of this study are to determine whether peginterferon beta-1a, at 1 year when compared with placebo, is effective in reducing the total number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans, reducing the proportion of subjects who relapse, and slowing the progression of disability.
    Protection of trial subjects
    During the first 6 weeks of treatment year 1 and again in treatment year 2, subjects were to complete dosing in the clinic; thereafter, dosing was to occur at home, and subjects were asked to attend clinic visits for collection of assessment data. If subjects experienced disease progression or relapses and wished to discontinue study treatment, recommended rules for rescue medication (switching to open-label treatment alternative approved MS medications) were defined in the protocol. To mitigate flu-like symptoms, all subjects randomized to receive peginterferon beta-1a treatment started dosing with a lower dose (starting dose of 63 mcg) and increased the dose every 2 weeks to the target dose of 125 mcg. The titration was performed in a blinded fashion. In order to relieve flu-like symptoms for the first 26 weeks in the study, all subjects were instructed to take acetaminophen, ibuprofen, nonsteroidal anti-inflammatory drugs (NSAIDS) or naproxen prior to injection and for the 24 hours following each study treatment injection at the recommended doses and frequencies per local labels. Additional doses of these protocol-designated products could be taken after 24 hours within the maximum daily dosage recommended per local labels.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jun 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Ukraine: 189
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 70
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Colombia: 18
    Country: Number of subjects enrolled
    Croatia: 14
    Country: Number of subjects enrolled
    Czech Republic: 38
    Country: Number of subjects enrolled
    Estonia: 23
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Georgia: 19
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    India: 170
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    New Zealand: 18
    Country: Number of subjects enrolled
    Peru: 25
    Country: Number of subjects enrolled
    Poland: 386
    Country: Number of subjects enrolled
    Romania: 48
    Country: Number of subjects enrolled
    Russian Federation: 145
    Country: Number of subjects enrolled
    Serbia: 134
    Worldwide total number of subjects
    1516
    EEA total number of subjects
    717
    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)
    1516
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The Screening Visit was to occur within 6 weeks prior to randomization (Baseline). The Screening period was to start on the day the subject signed the informed consent form (ICF).

    Period 1
    Period 1 title
    Treatment Year 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Year 1: Placebo
    Arm description
    Placebo every 2 weeks for 48 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL pre-filled syringes, self-administered by subcutaneous injection

    Arm title
    Year 1: Peginterferon Beta-1a Q4W
    Arm description
    125 mcg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated interferon beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    interferon beta-1a, Plegridy, PEG IFN ß-1a
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL of 0.25 mg/mL (125 mcg dose), self-administered by subcutaneous injection

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL pre-filled syringes, self-administered by subcutaneous injection.

    Arm title
    Year 1: Peginterferon Beta-1a Q2W
    Arm description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated interferon beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    interferon beta-1a, Plegridy, PEG IFN ß-1a
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL of 0.25 mg/mL (125 mcg dose), self administered by subcutaneous injection.

    Number of subjects in period 1 [1]
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
    Started
    500
    500
    512
    Completed Year 1 Study Treatment
    456
    438
    438 [2]
    Completed
    456
    438
    439
    Not completed
    44
    62
    73
         Physician decision
    -
    1
    3
         Not specified
    4
    2
    7
         Adverse event, serious fatal
    2
    1
    1
         Adverse event, non-fatal
    4
    22
    24
         Consent withdrawn by subject
    30
    32
    36
         Lost to follow-up
    4
    4
    2
    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: All efficacy endpoints were evaluated on the intent-to-treat (ITT) population, defined as all subjects who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo). The 1512 subjects who received at least 1 dose of study treatment comprised the ITT and safety population, and are presented in this subject disposition.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 1 subject in the Year 1: Peginterferon Beta-1a Q2W arm discontinued treatment before end of study period but remained to complete follow-up.
    Period 2
    Period 2 title
    Treatment Year 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Year 2: Placebo Followed by Peginterferon Beta-1a Q4W
    Arm description
    Subjects from Year 1 Placebo group were re-randomized to receive peginterferon beta-1a treatment with 125 mcg peginterfeon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated interferon beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    interferon beta-1a, Plegridy, PEG IFN ß-1a
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL of 0.25 mg/mL (125 mcg dose), self-administered by subcutaneous injection.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL pre-filled syringes, self-administered by subcutaneous injection.

    Arm title
    Year 2: Placebo Followed by Peginterferon Beta-1a Q2W
    Arm description
    Subjects from Year 1 Placebo group were re-randomized to receive peginterferon beta-1a treatment with 125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated interferon beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    interferon beta-1a, Plegridy, PEG IFN ß-1a
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL of 0.25 mg/mL (125 mcg dose), self administered by subcutaneous injection.

    Arm title
    Year 2: Peginterferon Beta-1a Q4W
    Arm description
    125 mcg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated interferon beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    interferon beta-1a, Plegridy, PEG IFN ß-1a
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL of 0.25 mg/mL (125 mcg dose), self-administered by subcutaneous injection.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL pre-filled syringes, self-administered by subcutaneous injection

    Arm title
    Year 2: Peginterferon Beta-1a Q2W
    Arm description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated interferon beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    interferon beta-1a, Plegridy, PEG IFN ß-1a
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL of 0.25 mg/mL (125 mcg dose), self administered by subcutaneous injection.

    Number of subjects in period 2 [3]
    Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
    Started
    228
    228
    438
    438
    Completed Year 2 Study Treatment
    200
    196
    391
    411
    Completed
    198
    193
    391
    409
    Not completed
    30
    35
    47
    29
         Physician decision
    -
    2
    6
    3
         Not specified
    2
    3
    1
    -
         Adverse event, serious fatal
    1
    -
    -
    3
         Adverse event, non-fatal
    9
    8
    11
    6
         Consent withdrawn by subject
    17
    18
    27
    13
         Lost to follow-up
    1
    4
    2
    4
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 subject in the Year 1: Peginterferon Beta-1a Q2W arm discontinued treatment before end of study period but remained to complete follow-up. This subject did not enter Year 2 treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Year 1: Placebo
    Reporting group description
    Placebo every 2 weeks for 48 weeks.

    Reporting group title
    Year 1: Peginterferon Beta-1a Q4W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 1: Peginterferon Beta-1a Q2W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.

    Reporting group values
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Total
    Number of subjects
    500 500 512 1512
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    500 500 512 1512
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.3 ± 9.74 36.4 ± 9.87 36.5 ± 9.8 -
    Gender categorical
    Units: Subjects
        Female
    358 352 361 1071
        Male
    142 148 151 441
    Expanded Disability Status Scale (EDSS)
    The EDSS measures the disability status of people with multiple sclerosis (MS) on a scale that ranges from 0 to 10. The range of main categories include 0 (normal neurologic exam), to 5 (ambulatory without aid or rest for 200 meters/disability severe enough to impair full daily activities), to 10 (death due to MS).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.44 ± 1.18 2.48 ± 1.244 2.47 ± 1.255 -

    End points

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    End points reporting groups
    Reporting group title
    Year 1: Placebo
    Reporting group description
    Placebo every 2 weeks for 48 weeks.

    Reporting group title
    Year 1: Peginterferon Beta-1a Q4W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 1: Peginterferon Beta-1a Q2W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
    Reporting group title
    Year 2: Placebo Followed by Peginterferon Beta-1a Q4W
    Reporting group description
    Subjects from Year 1 Placebo group were re-randomized to receive peginterferon beta-1a treatment with 125 mcg peginterfeon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 2: Placebo Followed by Peginterferon Beta-1a Q2W
    Reporting group description
    Subjects from Year 1 Placebo group were re-randomized to receive peginterferon beta-1a treatment with 125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.

    Reporting group title
    Year 2: Peginterferon Beta-1a Q4W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 2: Peginterferon Beta-1a Q2W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.

    Primary: Annualized Relapse Rate (ARR) at 1 Year

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    End point title
    Annualized Relapse Rate (ARR) at 1 Year
    End point description
    A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by an independent neurology evaluation committee (INEC) are included in the analysis. Data after participants switched to alternative multiple sclerosis (MS) medications are exlcuded. Data were analyzed using negative binomial regression, adjusted for baseline Expanded Disability Status Scale (EDSS) score (<4 versus > or = 4), baseline age (<40 versus > or =40 years), and baseline relapse rate (number of relapses in 3 years prior to study entry divided by 3).
    End point type
    Primary
    End point timeframe
    1 Year
    End point values
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
    Number of subjects analysed
    500
    500
    512
    Units: Relapses per person-years
        number (confidence interval 95%)
    0.397 (0.328 to 0.481)
    0.288 (0.234 to 0.355)
    0.256 (0.206 to 0.318)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q4W
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0114
    Method
    Negative Binomial Regression
    Parameter type
    Rate Ratio
    Point estimate
    0.725
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.565
         upper limit
    0.93
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q2W
    Number of subjects included in analysis
    1012
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Negative Binomial Regression
    Parameter type
    Rate Ratio
    Point estimate
    0.644
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.831
    Variability estimate
    Standard error of the mean

    Secondary: Number of New or Newly Enlarging T2 Hyperintense Lesions at 1 Year

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    End point title
    Number of New or Newly Enlarging T2 Hyperintense Lesions at 1 Year
    End point description
    Number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans. Data observed after participants switched to alternative MS medications are excluded. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions.
    End point type
    Secondary
    End point timeframe
    1 Year
    End point values
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
    Number of subjects analysed
    476 [1]
    462 [2]
    457 [3]
    Units: lesions
        number (confidence interval 95%)
    10.9 (9.6 to 12.5)
    7.9 (6.9 to 9)
    3.6 (3.1 to 4.2)
    Notes
    [1] - ITT population, with at least 1 post-baseline assessment.
    [2] - ITT population, with at least 1 post-baseline assessment.
    [3] - ITT population, with at least 1 post-baseline assessment.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q4W
    Number of subjects included in analysis
    938
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008
    Method
    Negative Binomial Regression
    Parameter type
    Lesion Mean Ratio
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    0.87
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Year 1: Peginterferon Beta-1a Q2W v Year 1: Placebo
    Number of subjects included in analysis
    933
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative Binomial Regression
    Parameter type
    Lesion Mean Ratio
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    0.4
    Variability estimate
    Standard error of the mean

    Secondary: Proportion of Subjects Relapsed at 1 Year

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    End point title
    Proportion of Subjects Relapsed at 1 Year
    End point description
    A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by INEC were included in the analysis. Estimated proportion of subjects relapsed is based on the Kaplan-Meier product limit method.
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
    Number of subjects analysed
    500
    500
    512
    Units: Proportion of participants
        number (not applicable)
    0.291
    0.222
    0.187
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q4W
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [4]
    Method
    Cox Proportion Hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    0.95
    Variability estimate
    Standard error of the mean
    Notes
    [4] - Based on Cox Proportion Hazards model, adjusted for baseline EDSS (<4 versus > or = 4), age (<40 versus > or = 40 years), baseline relapse rate, and baseline Gd enhancing lesions (presence versus absence).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q2W
    Number of subjects included in analysis
    1012
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [5]
    Method
    Cox Proportion Hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    0.8
    Variability estimate
    Standard error of the mean
    Notes
    [5] - Based on Cox Proportion Hazards model, adjusted for baseline EDSS (<4 versus > or = 4), age (<40 versus > or = 40 years), baseline relapse rate, and baseline Gd enhancing lesions (presence versus absence).

    Secondary: Estimated Proportion of Subjects With Sustained Disability Progression at 1 Year

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    End point title
    Estimated Proportion of Subjects With Sustained Disability Progression at 1 Year
    End point description
    Sustained disability progression is defined as: at least a 1.0 point increase on the EDSS from baseline EDSS > or = 1.0 that is sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks. The EDSS measures the disability status of people with MS on a scale that ranges from 0 to 10. The range of main categories include 0 (normal neurologic examination), to 5 (ambulatory without aid or rest for 200 meters/disability severe enough to impair full daily activities), to 10 (death due to MS). Estimated proportion of subjects with progression based on the Kaplan-Meier product limit method.
    End point type
    Secondary
    End point timeframe
    1 Year
    End point values
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
    Number of subjects analysed
    500
    500
    512
    Units: Proportion of participants
        number (not applicable)
    0.105
    0.068
    0.068
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q4W
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.038 [6]
    Method
    Cox Proportion Hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.97
    Variability estimate
    Standard error of the mean
    Notes
    [6] - Based on Cox Proportion Hazards model, adjusted for baseline EDSS (<4 versus > or = 4), age (<40 versus > or = 40 years).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Year 1: Placebo v Year 1: Peginterferon Beta-1a Q2W
    Number of subjects included in analysis
    1012
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0383 [7]
    Method
    Cox Proportion Hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.97
    Variability estimate
    Standard error of the mean
    Notes
    [7] - Based on Cox Proportion Hazards model, adjusted for baseline EDSS (<4 versus > or = 4), age (<40 versus > or = 40 years).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening through Week 96 (treatment period), plus 4 weeks (+/- 5 days) follow-up
    Adverse event reporting additional description
    One subject, randomized to placebo followed by Q4W, received 1 wrong dosing kit during Year 1, and was mistakenly distributed with 1 Q2W kit, therefore receiving study drug in Weeks 20 and 22 instead of placebo. For Year 1 safety tables, this subject was grouped with Q2W, and for Year 2 safety tables, this subject was grouped with Q4W.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Year 1: Placebo
    Reporting group description
    Placebo every 2 weeks for 48 weeks.

    Reporting group title
    Year 1: Peginterferon Beta-1a Q4W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 1: Peginterferon Beta-1a Q2W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.

    Reporting group title
    Year 2: Placebo Followed by Peginterferon Beta-1a Q4W
    Reporting group description
    Subjects from Year 1 Placebo group were re-randomized to receive peginterferon beta-1a treatment with 125 mcg peginterfeon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 2: Placebo Followed by Peginterferon Beta-1a Q2W
    Reporting group description
    Subjects from Year 1 Placebo group were re-randomized to receive peginterferon beta-1a treatment with 125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.

    Reporting group title
    Year 2: Peginterferon Beta-1a Q4W
    Reporting group description
    125 mcg peginterfeon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Subjects received a placebo injection 2 weeks after each active injection (in order to maintain the blind with the Q2W arm).

    Reporting group title
    Year 2: Peginterferon Beta-1a Q2W
    Reporting group description
    125 mcg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.

    Serious adverse events
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    76 / 499 (15.23%)
    70 / 500 (14.00%)
    55 / 513 (10.72%)
    42 / 227 (18.50%)
    36 / 228 (15.79%)
    67 / 439 (15.26%)
    39 / 438 (8.90%)
         number of deaths (all causes)
    2
    1
    1
    1
    0
    0
    3
         number of deaths resulting from adverse events
    0
    0
    0
    1
    0
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign vulval neoplasm
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion incomplete
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Conversion disorder
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Personality disorder
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 499 (0.20%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectropion of cervix
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymal cyst
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic adhesions
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine cervical erosion
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    2 / 439 (0.46%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Bile duct stone
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Bulbar palsy
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    57 / 499 (11.42%)
    47 / 500 (9.40%)
    34 / 513 (6.63%)
    27 / 227 (11.89%)
    21 / 228 (9.21%)
    45 / 439 (10.25%)
    25 / 438 (5.71%)
         occurrences causally related to treatment / all
    1 / 76
    2 / 61
    0 / 37
    3 / 31
    0 / 22
    2 / 50
    0 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis cranial
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyelitis optica
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal strangulation
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Micturition disorder
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enthesopathy
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 499 (0.20%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis gangrenous
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myometritis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    1 / 439 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 499 (0.20%)
    2 / 500 (0.40%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    1 / 227 (0.44%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 499 (0.00%)
    1 / 500 (0.20%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 499 (0.20%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 499 (0.20%)
    2 / 500 (0.40%)
    0 / 513 (0.00%)
    3 / 227 (1.32%)
    1 / 228 (0.44%)
    1 / 439 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    1 / 3
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    1 / 513 (0.19%)
    0 / 227 (0.00%)
    1 / 228 (0.44%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral tracheitis
         subjects affected / exposed
    0 / 499 (0.00%)
    0 / 500 (0.00%)
    0 / 513 (0.00%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    378 / 499 (75.75%)
    466 / 500 (93.20%)
    472 / 513 (92.01%)
    190 / 227 (83.70%)
    206 / 228 (90.35%)
    373 / 439 (84.97%)
    367 / 438 (83.79%)
    Investigations
    Body temperature increased
         subjects affected / exposed
    27 / 499 (5.41%)
    51 / 500 (10.20%)
    60 / 513 (11.70%)
    5 / 227 (2.20%)
    10 / 228 (4.39%)
    19 / 439 (4.33%)
    24 / 438 (5.48%)
         occurrences all number
    24
    142
    228
    22
    63
    67
    128
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 499 (2.61%)
    19 / 500 (3.80%)
    29 / 513 (5.65%)
    13 / 227 (5.73%)
    14 / 228 (6.14%)
    17 / 439 (3.87%)
    13 / 438 (2.97%)
         occurrences all number
    13
    22
    34
    16
    15
    26
    19
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    31 / 499 (6.21%)
    26 / 500 (5.20%)
    34 / 513 (6.63%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    44
    37
    56
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    28 / 499 (5.61%)
    26 / 500 (5.20%)
    21 / 513 (4.09%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    34
    35
    29
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    165 / 499 (33.07%)
    206 / 500 (41.20%)
    225 / 513 (43.86%)
    70 / 227 (30.84%)
    64 / 228 (28.07%)
    122 / 439 (27.79%)
    126 / 438 (28.77%)
         occurrences all number
    778
    1143
    1415
    278
    516
    699
    1000
    Multiple sclerosis relapse
         subjects affected / exposed
    154 / 499 (30.86%)
    111 / 500 (22.20%)
    90 / 513 (17.54%)
    50 / 227 (22.03%)
    52 / 228 (22.81%)
    95 / 439 (21.64%)
    63 / 438 (14.38%)
         occurrences all number
    200
    133
    123
    57
    63
    125
    81
    Dizziness
         subjects affected / exposed
    30 / 499 (6.01%)
    22 / 500 (4.40%)
    35 / 513 (6.82%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    45
    49
    85
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    23 / 499 (4.61%)
    22 / 500 (4.40%)
    26 / 513 (5.07%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    42
    31
    35
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    30 / 499 (6.01%)
    29 / 500 (5.80%)
    17 / 513 (3.31%)
    13 / 227 (5.73%)
    11 / 228 (4.82%)
    10 / 439 (2.28%)
    11 / 438 (2.51%)
         occurrences all number
    46
    39
    38
    27
    17
    22
    20
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    33 / 499 (6.61%)
    282 / 500 (56.40%)
    315 / 513 (61.40%)
    119 / 227 (52.42%)
    135 / 228 (59.21%)
    211 / 439 (48.06%)
    212 / 438 (48.40%)
         occurrences all number
    67
    1716
    3300
    773
    1521
    1426
    2981
    Influenza like illness
         subjects affected / exposed
    63 / 499 (12.63%)
    234 / 500 (46.80%)
    238 / 513 (46.39%)
    95 / 227 (41.85%)
    106 / 228 (46.49%)
    199 / 439 (45.33%)
    192 / 438 (43.84%)
         occurrences all number
    335
    1629
    2492
    733
    1290
    1526
    2384
    Pyrexia
         subjects affected / exposed
    75 / 499 (15.03%)
    218 / 500 (43.60%)
    227 / 513 (44.25%)
    66 / 227 (29.07%)
    66 / 228 (28.95%)
    138 / 439 (31.44%)
    136 / 438 (31.05%)
         occurrences all number
    211
    1150
    1578
    362
    434
    804
    1070
    Chills
         subjects affected / exposed
    23 / 499 (4.61%)
    92 / 500 (18.40%)
    88 / 513 (17.15%)
    28 / 227 (12.33%)
    29 / 228 (12.72%)
    52 / 439 (11.85%)
    41 / 438 (9.36%)
         occurrences all number
    67
    419
    379
    91
    157
    252
    203
    Injection site pain
         subjects affected / exposed
    15 / 499 (3.01%)
    67 / 500 (13.40%)
    78 / 513 (15.20%)
    25 / 227 (11.01%)
    25 / 228 (10.96%)
    32 / 439 (7.29%)
    45 / 438 (10.27%)
         occurrences all number
    18
    148
    287
    73
    71
    77
    172
    Asthenia
         subjects affected / exposed
    38 / 499 (7.62%)
    70 / 500 (14.00%)
    68 / 513 (13.26%)
    24 / 227 (10.57%)
    10 / 228 (4.39%)
    39 / 439 (8.88%)
    40 / 438 (9.13%)
         occurrences all number
    117
    248
    316
    105
    48
    137
    226
    Injection site pruritus
         subjects affected / exposed
    6 / 499 (1.20%)
    56 / 500 (11.20%)
    70 / 513 (13.65%)
    17 / 227 (7.49%)
    26 / 228 (11.40%)
    24 / 439 (5.47%)
    47 / 438 (10.73%)
         occurrences all number
    19
    130
    328
    58
    130
    63
    323
    Fatigue
         subjects affected / exposed
    49 / 499 (9.82%)
    55 / 500 (11.00%)
    52 / 513 (10.14%)
    10 / 227 (4.41%)
    21 / 228 (9.21%)
    26 / 439 (5.92%)
    32 / 438 (7.31%)
         occurrences all number
    87
    125
    153
    18
    71
    88
    150
    Pain
         subjects affected / exposed
    16 / 499 (3.21%)
    29 / 500 (5.80%)
    25 / 513 (4.87%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    77
    84
    69
    0
    0
    0
    0
    Hyperthermia
         subjects affected / exposed
    5 / 499 (1.00%)
    26 / 500 (5.20%)
    22 / 513 (4.29%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    25
    155
    132
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    43 / 499 (8.62%)
    32 / 500 (6.40%)
    27 / 513 (5.26%)
    9 / 227 (3.96%)
    11 / 228 (4.82%)
    17 / 439 (3.87%)
    14 / 438 (3.20%)
         occurrences all number
    74
    46
    73
    18
    17
    29
    22
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    31 / 499 (6.21%)
    43 / 500 (8.60%)
    45 / 513 (8.77%)
    9 / 227 (3.96%)
    14 / 228 (6.14%)
    16 / 439 (3.64%)
    27 / 438 (6.16%)
         occurrences all number
    52
    88
    105
    18
    37
    24
    102
    Vomiting
         subjects affected / exposed
    11 / 499 (2.20%)
    37 / 500 (7.40%)
    26 / 513 (5.07%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    15
    63
    35
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    23 / 499 (4.61%)
    22 / 500 (4.40%)
    18 / 513 (3.51%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    28
    26
    19
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    21 / 499 (4.21%)
    25 / 500 (5.00%)
    22 / 513 (4.29%)
    6 / 227 (2.64%)
    13 / 228 (5.70%)
    18 / 439 (4.10%)
    17 / 438 (3.88%)
         occurrences all number
    21
    28
    28
    6
    14
    19
    24
    Insomnia
         subjects affected / exposed
    19 / 499 (3.81%)
    18 / 500 (3.60%)
    28 / 513 (5.46%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    29
    28
    49
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    30 / 499 (6.01%)
    97 / 500 (19.40%)
    99 / 513 (19.30%)
    27 / 227 (11.89%)
    27 / 228 (11.84%)
    60 / 439 (13.67%)
    58 / 438 (13.24%)
         occurrences all number
    96
    396
    661
    89
    481
    154
    309
    Back pain
         subjects affected / exposed
    57 / 499 (11.42%)
    64 / 500 (12.80%)
    62 / 513 (12.09%)
    11 / 227 (4.85%)
    19 / 228 (8.33%)
    31 / 439 (7.06%)
    32 / 438 (7.31%)
         occurrences all number
    126
    132
    132
    130
    18
    69
    69
    Arthralgia
         subjects affected / exposed
    35 / 499 (7.01%)
    54 / 500 (10.80%)
    58 / 513 (11.31%)
    23 / 227 (10.13%)
    14 / 228 (6.14%)
    33 / 439 (7.52%)
    33 / 438 (7.53%)
         occurrences all number
    54
    170
    296
    114
    61
    58
    254
    Pain in extremity
         subjects affected / exposed
    48 / 499 (9.62%)
    53 / 500 (10.60%)
    44 / 513 (8.58%)
    10 / 227 (4.41%)
    14 / 228 (6.14%)
    23 / 439 (5.24%)
    31 / 438 (7.08%)
         occurrences all number
    87
    107
    110
    17
    53
    45
    64
    Muscular weakness
         subjects affected / exposed
    18 / 499 (3.61%)
    23 / 500 (4.60%)
    22 / 513 (4.29%)
    12 / 227 (5.29%)
    12 / 228 (5.26%)
    18 / 439 (4.10%)
    13 / 438 (2.97%)
         occurrences all number
    20
    45
    33
    25
    34
    40
    33
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    77 / 499 (15.43%)
    69 / 500 (13.80%)
    54 / 513 (10.53%)
    22 / 227 (9.69%)
    17 / 228 (7.46%)
    45 / 439 (10.25%)
    47 / 438 (10.73%)
         occurrences all number
    121
    105
    95
    29
    32
    56
    64
    Urinary tract infection
         subjects affected / exposed
    20 / 499 (4.01%)
    28 / 500 (5.60%)
    28 / 513 (5.46%)
    10 / 227 (4.41%)
    11 / 228 (4.82%)
    31 / 439 (7.06%)
    29 / 438 (6.62%)
         occurrences all number
    29
    39
    38
    11
    18
    37
    39
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 499 (5.41%)
    16 / 500 (3.20%)
    28 / 513 (5.46%)
    0 / 227 (0.00%)
    0 / 228 (0.00%)
    0 / 439 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    41
    22
    37
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2009
    The protocol was revised primarily to clarify study procedures and some of the description of the statistical analysis methods.
    16 Apr 2010
    The protocol was revised primarily to adjust the holding and stopping rules for study treatment dosing. The language regarding the monitoring of hepatic safety was strengthened following an in depth review of the safety experience for interferons, including interferon beta-1a. Thus, the guidelines (Table 1, Laboratory Criteria Requiring Withholding or Permanent Discontinuation of Blinded Study Treatment with BIIB017/Placebo) for re-starting study treatment after a >5 fold elevation in transaminases (ALT and AST) were added to the study Holding and Stopping rules.
    14 Mar 2011
    The protocol was revised primarily to increase the study sample size. The number of planned subjects was increased from 1260 subjects to approximately 1500 subjects. As permitted by the protocol, the pooled 1-year annualized relapse rate was monitored and the placebo 1-year annualized relapse rate was estimated by back-calculating from the pooled annualized relapse rate, and the assumed treatment effect. As a result of this monitoring, the sample size was increased from 420 to 500 subjects per treatment group. The planned sample sizes for PK/PD sample collections were accordingly increased. Inclusion Criterion No. 2 was updated. The age limit for subject inclusion into the study was increased to optimize enrollment and to better reflect the age range of the treated MS population. The Exclusion Criterion No. 11, known history or positive test results for hepatitis was updated in order to prevent the inappropriate exclusion of patients from the study. Testing for HBsAb was added as a screening assessment to determine if a patient had cleared a hepatitis B infection. Based on the CDC’s interpretation of the hepatitis B serology panel (CDC, 2007), subjects who were positive for HBcAb would now only be excluded if they were also negative for HBsAb IgG. Subjects who were positive for HCV Ab were to continue to be excluded from the study, as were all subjects who were positive for HBsAg. Exclusion Criterion No. 16, which provides a table of treatment agents that were prohibited for eligibility, was modified to include the recently approved MS therapy, fingolimod.
    27 Mar 2012
    The protocol was revised primarily to move the MSIS-29 outcome measure from the secondary objectives to the additional objectives. Unlike the other specified primary and secondary objectives and endpoints (measures of relapses, MRI lesions, and disease progression), the MSIS-29, a patient reported measure of health status, has not yet been fully established as a direct measure of MS disease activity. As such, inclusion of this assessment in the key secondary endpoints may not be appropriate. Analysis for Primary Endpoint, EDSS (≤3.5 or >3.5) was changed to (<4 and ≥4) for clarity. Given the ordinal nature of the EDSS scale, the revised cutoff is logically equivalent to that previously described; therefore, this change doesn’t affect the analysis methods.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24794721
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