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    Clinical Trial Results:
    Multicenter, Double-blind, Randomized, Parallel-group, Monotherapy, Active-control Study to Determine the Efficacy and Safety of Daclizumab High Yield Process (DAC HYP) Versus Avonex® (Interferon Beta-1a) in Patients With Relapsing-Remitting Multiple Sclerosis

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2009-012500-11
    Trial protocol
    IE   FR   DE   CZ   HU   FI   SE   ES   GB   GR   IT   DK   SI  
    Global end of trial date
    28 Jul 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    19 Feb 2016
    First version publication date
    12 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT – Results

    Trial information

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    Trial identification
    Sponsor protocol code
    205MS301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01064401
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective is to test the superiority of Daclizumab High Yield Process (DAC HYP) compared with interferon β-1a (IFN β-1a) in preventing multiple sclerosis (MS) relapse in participants with relapsing remitting multiple sclerosis. The secondary study objectives are to test the superiority of DAC HYP compared with IFN β-1a in slowing functional decline and disability progression and maintaining quality of life in this participant population.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 May 2010
    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
    Poland: 451
    Country: Number of subjects enrolled
    United States: 217
    Country: Number of subjects enrolled
    Russian Federation: 198
    Country: Number of subjects enrolled
    Ukraine: 129
    Country: Number of subjects enrolled
    Serbia: 111
    Country: Number of subjects enrolled
    Italy: 97
    Country: Number of subjects enrolled
    Czech Republic: 85
    Country: Number of subjects enrolled
    United Kingdom: 70
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    India: 50
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hungary: 36
    Country: Number of subjects enrolled
    Brazil: 34
    Country: Number of subjects enrolled
    Romania: 33
    Country: Number of subjects enrolled
    Sweden: 31
    Country: Number of subjects enrolled
    Greece: 26
    Country: Number of subjects enrolled
    Argentina: 24
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Moldova, Republic of: 17
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Georgia: 5
    Country: Number of subjects enrolled
    Finland: 3
    Worldwide total number of subjects
    1841
    EEA total number of subjects
    994
    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)
    1841
    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 study included a 4-week screening period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Interferon beta-1a
    Arm description
    Interferon beta-1a (IFN β-1a) 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks
    Arm type
    Active comparator

    Investigational medicinal product name
    Interferon beta-1A
    Investigational medicinal product code
    Other name
    Avonex
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Avonex was supplied in treatment kits that were dispensed to subjects at each visit and contained a sufficient supply of Avonex prefilled syringes and IM needles for each dosing interval. Subjects were instructed on how to perform injections at home.

    Investigational medicinal product name
    Placebo to DAC HYP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo to DAC HYP was prepared and administered in an identical manner to DAC HYP.

    Arm title
    Daclizumab High Yield Process
    Arm description
    DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Daclizumab HYP
    Investigational medicinal product code
    BIIB019
    Other name
    DAC HYP
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The individual preparing the DAC HYP carefully reviewed the instructions provided in the Directions for Handling and Administration, which superseded all other references (e.g., the DAC HYP Investigator Brochure), and DAC HYP was administered by staff in the clinic at the monthly visits. Subjects received SC injections of DAC HYP in one or more of the following locations: the back of the upper arm, the thigh, or the abdomen.

    Investigational medicinal product name
    Placebo to Avonex
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Placebo to Avonex was supplied in treatment kits, which was dispensed to subjects at each visit and contained a sufficient supply of Avonex placebo prefilled syringes and IM needles for each dosing interval. Subjects were instructed on how to perform injections at home.

    Number of subjects in period 1
    Interferon beta-1a Daclizumab High Yield Process
    Started
    922
    919
    Completed
    694
    724
    Not completed
    228
    195
         Death
    4
    -
         Physician decision
    4
    6
         Adverse event
    47
    56
         Non-compliance
    7
    8
         Lack of efficacy
    46
    23
         Pregnancy
    4
    7
         Not specified
    2
    1
         Consent withdrawn by subject
    98
    80
         Site closure
    4
    5
         Lost to follow-up
    12
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Interferon beta-1a
    Reporting group description
    Interferon beta-1a (IFN β-1a) 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks

    Reporting group title
    Daclizumab High Yield Process
    Reporting group description
    DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks

    Reporting group values
    Interferon beta-1a Daclizumab High Yield Process Total
    Number of subjects
    922 919 1841
    Age categorical
    Units: Subjects
        18 to 19 years
    25 14 39
        20 to 29 years
    227 236 463
        30 to 39 years
    327 322 649
        40 to 49 years
    256 250 506
        50 to 55 years
    86 96 182
        > 55 years
    1 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    36.2 ± 9.32 36.4 ± 9.36 -
    Gender, Male/Female
    Units: participants
        Female
    627 625 1252
        Male
    295 294 589

    End points

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    End points reporting groups
    Reporting group title
    Interferon beta-1a
    Reporting group description
    Interferon beta-1a (IFN β-1a) 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks

    Reporting group title
    Daclizumab High Yield Process
    Reporting group description
    DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks

    Primary: Adjusted Annualized Relapse Rate (ARR)

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    End point title
    Adjusted Annualized Relapse Rate (ARR)
    End point description
    Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. Only relapses confirmed by Independent Neurology Evaluation Committee (INEC) are included in this analysis. Adjusted ARR was estimated from a negative binomial regression model adjusted for the baseline relapse rate, history of prior IFN beta use, baseline Expanded Disability Status Scale (EDSS; ≤ 2.5 vs > 2.5) and baseline age (≤ 35 vs > 35). Data after subjects switched to alternative MS medications are excluded.
    End point type
    Primary
    End point timeframe
    Up to 144 weeks
    End point values
    Interferon beta-1a Daclizumab High Yield Process
    Number of subjects analysed
    392 [1]
    260 [2]
    Units: relapses per person-years
        number (confidence interval 95%)
    0.393 (0.353 to 0.438)
    0.216 (0.191 to 0.244)
    Notes
    [1] - subject with a relapse; number of relapses analyzed = 643
    [2] - subject with a relapse; number of relapses analyzed = 402
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Daclizumab High Yield Process v Interferon beta-1a
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    negative binomial regression
    Parameter type
    rate ratio
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.469
         upper limit
    0.645
    Notes
    [3] - Estimated from a negative binomial regression model adjusted for the baseline relapse rate, history of prior IFN beta use, baseline EDSS (≤ 2.5 vs > 2.5) and baseline age (≤ 35 vs > 35).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Interferon beta-1a v Daclizumab High Yield Process
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    percent reduction
    Point estimate
    45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.5
         upper limit
    53.1

    Secondary: Adjusted Mean Number of New or Newly Enlarging T2 Hyperintense Lesions up to Week 96

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    End point title
    Adjusted Mean Number of New or Newly Enlarging T2 Hyperintense Lesions up to Week 96
    End point description
    Assessed by brain magnetic resonance imaging (MRI). Estimated from a negative binomial regression model, adjusted for baseline volume of T2 hyperintense lesions, history of prior IFN beta use and baseline age (≤ 35 vs > 35). To account for the timing of the MRI measurement, the logarithmic transformation of the scan number of the MRI assessment was included in the model as the 'offset' parameter. Observed data after subjects switched to alternative MS medications are excluded. Missing data are not imputed. Only observed new or newly enlarging T2 lesions at the last visit of the subject up to Week 96 visit are used in this analysis.
    End point type
    Secondary
    End point timeframe
    up to 96 weeks
    End point values
    Interferon beta-1a Daclizumab High Yield Process
    Number of subjects analysed
    841 [4]
    864 [5]
    Units: lesions
        arithmetic mean (confidence interval 95%)
    9.44 (8.46 to 10.54)
    4.31 (3.85 to 4.81)
    Notes
    [4] - subjects with baseline and at least 1 post-baseline MRI measurement
    [5] - subjects with baseline and at least 1 post-baseline MRI measurement
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Sustained Disability Progression at 144 Weeks

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    End point title
    Proportion of Subjects With Sustained Disability Progression at 144 Weeks
    End point description
    Sustained disability progression is defined as: at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from Baseline EDSS ≥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 multiple sclerosis on a scale that ranges from 0 to 10, with higher scores indicating more disability. Estimated proportion of subjects with progression is based on the Kaplan-Meier product limit method. Subjects were censored at the time of withdrawal/switch if they withdrew from study or switched to alternative MS medication without a progression. Subjects with a tentative progression at the End of Treatment Period Visit (or the last EDSS assessment prior to alternative MS start date) and no confirmation assessment were censored at their last EDSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline through 144 weeks
    End point values
    Interferon beta-1a Daclizumab High Yield Process
    Number of subjects analysed
    922
    919
    Units: proportion of participants
        number (not applicable)
    0.203
    0.162
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Relapse-free at Week 144

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    End point title
    Proportion of Subjects Relapse-free at Week 144
    End point description
    Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. Only relapses confirmed by INEC are included in this analysis. Data after subjects switched to alternative MS medications are excluded. The estimated proportion of subjects relapse-free at Week 144 is based on the Kaplan-Meier product limit method.
    End point type
    Secondary
    End point timeframe
    144 weeks
    End point values
    Interferon beta-1a Daclizumab High Yield Process
    Number of subjects analysed
    922
    919
    Units: proportion of participants
        number (not applicable)
    0.508
    0.673
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a ≥ 7.5 Point Worsening From Baseline in the Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score at 96 Weeks

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    End point title
    Percentage of Subjects With a ≥ 7.5 Point Worsening From Baseline in the Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score at 96 Weeks
    End point description
    The MSIS-29 is a 29-item disease-specific patient-reported outcome measure that has been developed and validated to examine the physical and psychological impact of MS from a patient’s perspective; it measures physical and psychological items. Worsening in the MSIS-29 physical score is defined as an increase of ≥ 7.5 points in the MSIS-29 physical score at 96 weeks compared to baseline. If a subject was missing data for less than 10 of the 20 items that make up the physical score, then the mean of the non-missing items were used for the missing items. If a subject was missing 10 or more of the 20 items that make up the physical score, or missing the questionnaire entirely, or if the questionnaire was completed after the subject switched to alternative MS medication, a random effects model was used to estimate the MSIS-29 physical score.
    End point type
    Secondary
    End point timeframe
    Baseline and 96 weeks
    End point values
    Interferon beta-1a Daclizumab High Yield Process
    Number of subjects analysed
    912 [6]
    906 [7]
    Units: percentage of subjects
        number (not applicable)
    23
    19
    Notes
    [6] - subjects with an assessment at baseline and Week 96
    [7] - subjects with an assessment at baseline and Week 96
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All events were collected from Baseline through Week 164 (end of Post-dosing period).
    Adverse event reporting additional description
    Treatment emergent events are reported. Events are considered treatment emergent if they occurred on or after the first dosing date and up to 180 days after the last dosing date.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    IFN beta-1a 30 mcg
    Reporting group description
    IFN β-1a 30 µg IM injection once weekly plus placebo to DAC HYP SC once every 4 weeks for 96 to 144 weeks

    Reporting group title
    DAC HYP 150 mg
    Reporting group description
    DAC HYP 150 mg subcutaneous (SC) injection once every 4 weeks plus placebo to IFN β-1a intramuscular (IM) injection once weekly for 96 to 144 weeks

    Serious adverse events
    IFN beta-1a 30 mcg DAC HYP 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    194 / 922 (21.04%)
    221 / 919 (24.05%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 922 (0.22%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 922 (0.22%)
    4 / 919 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 922 (0.11%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail avulsion
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 922 (0.22%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 922 (0.22%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 922 (0.22%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Smear cervix abnormal
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 922 (0.33%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Palpitations
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Dermoid cyst
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 922 (0.00%)
    5 / 919 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 922 (0.00%)
    3 / 919 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoid tissue hyperplasia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 922 (0.00%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 922 (0.11%)
    4 / 919 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    3 / 922 (0.33%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    124 / 922 (13.45%)
    97 / 919 (10.55%)
         occurrences causally related to treatment / all
    1 / 206
    3 / 150
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing-remitting multiple sclerosis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cystoid macular oedema
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 922 (0.11%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth cyst
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oroantral fistula
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 922 (0.00%)
    3 / 919 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 922 (0.00%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dermal cyst
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 922 (0.00%)
    3 / 919 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytoclastic vasculitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichenoid keratosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pityriasis rubra pilaris
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pustular psoriasis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus-like syndrome
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plica syndrome
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tetany
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 922 (0.00%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 922 (0.00%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis a
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ludwig angina
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroborreliosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 922 (0.22%)
    5 / 919 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reiter's syndrome
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Strongyloidiasis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 922 (0.22%)
    8 / 919 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 922 (0.11%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kawasaki's disease
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioplasty
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cystectomy
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal decompression
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign ovarian tumour
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 922 (0.00%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular seminoma (pure)
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 922 (0.11%)
    3 / 919 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 922 (0.11%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    3 / 922 (0.33%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed disturbance of emotion and conduct
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 922 (0.22%)
    3 / 919 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emotional distress
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 922 (0.11%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 922 (0.22%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial disorder
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 922 (0.11%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleurisy
         subjects affected / exposed
    1 / 922 (0.11%)
    0 / 919 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 922 (0.00%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 922 (0.33%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 922 (0.00%)
    1 / 919 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 922 (0.11%)
    2 / 919 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    IFN beta-1a 30 mcg DAC HYP 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    783 / 922 (84.92%)
    731 / 919 (79.54%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    66 / 922 (7.16%)
    69 / 919 (7.51%)
         occurrences all number
    86
    96
    Aspartate aminotransferase increased
         subjects affected / exposed
    44 / 922 (4.77%)
    48 / 919 (5.22%)
         occurrences all number
    51
    69
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    46 / 922 (4.99%)
    53 / 919 (5.77%)
         occurrences all number
    56
    68
    Oropharyngeal pain
         subjects affected / exposed
    41 / 922 (4.45%)
    69 / 919 (7.51%)
         occurrences all number
    53
    86
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    7 / 922 (0.76%)
    46 / 919 (5.01%)
         occurrences all number
    7
    58
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    37 / 922 (4.01%)
    48 / 919 (5.22%)
         occurrences all number
    58
    66
    Headache
         subjects affected / exposed
    175 / 922 (18.98%)
    159 / 919 (17.30%)
         occurrences all number
    925
    443
    Hypoaesthesia
         subjects affected / exposed
    54 / 922 (5.86%)
    54 / 919 (5.88%)
         occurrences all number
    76
    71
    Multiple sclerosis relapse
         subjects affected / exposed
    428 / 922 (46.42%)
    293 / 919 (31.88%)
         occurrences all number
    748
    480
    Paraesthesia
         subjects affected / exposed
    57 / 922 (6.18%)
    42 / 919 (4.57%)
         occurrences all number
    101
    59
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    55 / 922 (5.97%)
    37 / 919 (4.03%)
         occurrences all number
    232
    66
    Fatigue
         subjects affected / exposed
    76 / 922 (8.24%)
    69 / 919 (7.51%)
         occurrences all number
    125
    103
    Influenza like illness
         subjects affected / exposed
    345 / 922 (37.42%)
    88 / 919 (9.58%)
         occurrences all number
    3172
    166
    Injection site pain
         subjects affected / exposed
    102 / 922 (11.06%)
    96 / 919 (10.45%)
         occurrences all number
    376
    331
    Injection site erythema
         subjects affected / exposed
    47 / 922 (5.10%)
    40 / 919 (4.35%)
         occurrences all number
    243
    62
    Pyrexia
         subjects affected / exposed
    134 / 922 (14.53%)
    104 / 919 (11.32%)
         occurrences all number
    624
    170
    Psychiatric disorders
    Depression
         subjects affected / exposed
    56 / 922 (6.07%)
    72 / 919 (7.83%)
         occurrences all number
    68
    85
    Insomnia
         subjects affected / exposed
    54 / 922 (5.86%)
    42 / 919 (4.57%)
         occurrences all number
    62
    52
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    55 / 922 (5.97%)
    67 / 919 (7.29%)
         occurrences all number
    71
    82
    Nausea
         subjects affected / exposed
    46 / 922 (4.99%)
    46 / 919 (5.01%)
         occurrences all number
    60
    80
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    26 / 922 (2.82%)
    64 / 919 (6.96%)
         occurrences all number
    29
    80
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    62 / 922 (6.72%)
    71 / 919 (7.73%)
         occurrences all number
    113
    96
    Back pain
         subjects affected / exposed
    70 / 922 (7.59%)
    86 / 919 (9.36%)
         occurrences all number
    106
    146
    Myalgia
         subjects affected / exposed
    49 / 922 (5.31%)
    42 / 919 (4.57%)
         occurrences all number
    167
    67
    Pain in extremity
         subjects affected / exposed
    58 / 922 (6.29%)
    55 / 919 (5.98%)
         occurrences all number
    134
    90
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    43 / 922 (4.66%)
    61 / 919 (6.64%)
         occurrences all number
    48
    76
    Nasopharyngitis
         subjects affected / exposed
    197 / 922 (21.37%)
    226 / 919 (24.59%)
         occurrences all number
    319
    499
    Influenza
         subjects affected / exposed
    56 / 922 (6.07%)
    82 / 919 (8.92%)
         occurrences all number
    77
    113
    Oral herpes
         subjects affected / exposed
    44 / 922 (4.77%)
    57 / 919 (6.20%)
         occurrences all number
    63
    106
    Pharyngitis
         subjects affected / exposed
    69 / 922 (7.48%)
    77 / 919 (8.38%)
         occurrences all number
    89
    109
    Upper respiratory tract infection
         subjects affected / exposed
    124 / 922 (13.45%)
    148 / 919 (16.10%)
         occurrences all number
    183
    259
    Urinary tract infection
         subjects affected / exposed
    96 / 922 (10.41%)
    92 / 919 (10.01%)
         occurrences all number
    136
    150

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2011
    The primary reasons for this amendment to Protocol 205MS301 were to: - Increase subject monitoring for laboratory signals related to hepatic function (liver function tests [LFTs] will be assessed monthly throughout the treatment period), and update criteria for temporary suspension and discontinuation of study treatment for subjects who develop elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin. Subjects who must permanently discontinue study treatment due to elevated LFTs will be evaluated for possible toxicological, infectious, immunological, and metabolic causes of liver injury. - Provide additional guidance to Investigators on the evaluation and management of cutaneous events. - Increase the sample size for the study from 1500 to 1800 subjects based on recent clinical studies that suggested a lower annualized relapse rate for the IFN β-1a group.
    10 Mar 2012
    The primary reasons for this amendment to Protocol 205MS301 were to: - Prohibit concomitant treatment with medications that have an established association with hepatotoxicity or cutaneous hypersensitivity reactions. - Provide monthly liver function testing results to the Treating Neurologist prior to administration of study treatment.
    29 Apr 2013
    The primary reasons for this amendment to Protocol 205MS301 were to: - Modify the definition and rank ordering of some secondary and additional endpoints - Update the statistical analysis section in the protocol: In the protocol version 1 for Study 205MS301, it was stated that efficacy analyses in the trial would first be tested at the 0.04 significance level, and if they were negative, they would then be tested at the 0.01 significance level in the subgroup of subjects who were positive at Baseline for the DAC HYP response signature. Based on the results from exploratory analyses that were performed on Study 205MS201 biomarker data, and in accordance with the original design of Study 205MS301, the sponsor then amended protocol for Study 205MS301 on 29 April 2013 (approximately 11 months prior to the end of Study 205MS301 Treatment Period) to document this result, removed the reference to the response signature from the analysis plan, and clarifed that all efficacy analyses in Study 205MS301 would be performed at the standard 0.05 significance level.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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