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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of BG00012 in Subjects From the Asia-Pacific Region and Other Countries With Relapsing-Remitting Multiple Sclerosis

    Summary
    EudraCT number
    		 2013-004533-32
    Trial protocol
    		 CZ   PL  
    Global end of trial date
    04 Sep 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Sep 2019
    First version publication date
    19 Jun 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01838668
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, 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
    04 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of Part I of the study is to determine the efficacy of BG00012 on inflammatory brain magnetic resonance imaging (MRI) lesion activity (gadolinium [Gd]-enhancing lesions) when compared with placebo from 4 scans performed at Weeks 12, 16, 20, and 24 in subjects with relapsing-remitting multiple sclerosis (RRMS) including subjects from the Asia-Pacific region. The primary objective of Part II of this study is to evaluate the long-term safety profile of BG00012 in eligible subjects from Part I.
    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
    28 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 54 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    Japan: 115
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Taiwan: 8
    Worldwide total number of subjects
    225
    EEA total number of subjects
    82
    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)
    225
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included a Screening Period (maximum of 28 days). A total of 225 subjects were randomized; however, 1 subject in the BG00012 240 mg twice a day (BID) arm was not dosed.

    Pre-assignment period milestones
    Number of subjects started
    		 225
    Number of subjects completed
    		 224

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Randomized but not dosed: 1
    Period 1
    Period 1 title
    Part I (Double-blind Treatment Period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    BG00012 and placebo administration was double-blind. Placebo capsules matched BG00012 capsules in size, shape, color, and taste. Additionally, all subjects (including those receiving placebo) were dosed with the same number of capsules BID.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part I Placebo
    Arm description
    		 Subjects randomized to placebo BID began dosing at 1 placebo capsule orally BID for the first 7 days and escalated to 2 placebo capsules orally BID from Day 8 through Week 24 (end of Part I).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The pharmacist or designee dispensed at least a 4-week supply of study treatment to subjects at Baseline (Day 1/Enrollment Visit) and at each subsequent study visit through Week 24. Study treatment was not to be dispensed at Week 24 (except in the case of subjects continuing to Part II Extension Period) or at any Unscheduled Relapse Assessment Visit.

    Arm title
    		 Part I BG00012 240 mg BID
    Arm description
    		 Subjects randomized to BG00012 began dosing at 120 mg BG00012 (1 capsule orally BID) for the first 7 days and escalated to 240 mg BG00012 (2 capsules orally BID) from Day 8 through Week 24 (end of Part I).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF, Tecfidera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The pharmacist or designee dispensed at least a 4-week supply of study treatment to subjects at Baseline (Day 1/Enrollment Visit) and at each subsequent study visit through Week 24. Study treatment was not to be dispensed at Week 24 (except in the case of subjects continuing to Part II Extension Period) or at any Unscheduled Relapse Assessment Visit.

    Number of subjects in period 1 [1]
    		Part I Placebo Part I BG00012 240 mg BID
    Started
    113
    111
    Subjects dosed in Part I
    113
    111
    Completed study drug in Part I
    107 [2]
    105
    Completed study in Part I
    108
    105
    Completed
    108
    105
    Not completed
    5
    6
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    2
    1
         Not specified
    -
    4
    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: 1 subject in the BG00012 240 mg BID arm was not dosed and is not included.
    [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: The number of subjects who completed study drug is included for reference. 1 subject did not complete study drug but did complete the study.
    Period 2
    Period 2 title
    Part II (Open-label Treatment Period)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part II: Placebo/BG00012 240 mg BID (Switchers):
    Arm description
    		 “PBO/BG12” – Subjects who received placebo in Part I before receiving BG00012 240 milligram (mg) BID in Part II for up to 4.5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF, Tecfidera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The pharmacist or designee dispensed at least a 4-week supply of study treatment to subjects at Baseline (Day 1/Enrollment Visit) and at each subsequent study visit through Week 24. Study treatment was not to be dispensed at Week 24 (except in the case of subjects continuing to Part II Extension Period) or at any Unscheduled Relapse Assessment Visit.

    Arm title
    		 Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Arm description
    		 “BG12/BG12” - Subjects who received BG00012 240 mg BID in Part I, continued receiving BG00012 in Part II for up to 4.5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF, Tecfidera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The pharmacist or designee dispensed at least a 4-week supply of study treatment to subjects at Baseline (Day 1/Enrollment Visit) and at each subsequent study visit through Week 24. Study treatment was not to be dispensed at Week 24 (except in the case of subjects continuing to Part II Extension Period) or at any Unscheduled Relapse Assessment Visit.

    Number of subjects in period 2
    		Part II: Placebo/BG00012 240 mg BID (Switchers): Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Started
    108
    105
    Completed
    0
    2
    Not completed
    108
    103
         Adverse event, non-fatal
    9
    4
         Investigator decision
    2
    3
         Lost to follow-up
    1
    -
         Reason not specified
    83
    82
         Consent withdrawn
    13
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part I Placebo
    Reporting group description
    		 Subjects randomized to placebo BID began dosing at 1 placebo capsule orally BID for the first 7 days and escalated to 2 placebo capsules orally BID from Day 8 through Week 24 (end of Part I).

    Reporting group title
    Part I BG00012 240 mg BID
    Reporting group description
    		 Subjects randomized to BG00012 began dosing at 120 mg BG00012 (1 capsule orally BID) for the first 7 days and escalated to 240 mg BG00012 (2 capsules orally BID) from Day 8 through Week 24 (end of Part I).

    Reporting group values
    		 Part I Placebo Part I BG00012 240 mg BID Total
    Number of subjects
    		 113 111 224
    Age categorical
    Units: Subjects
        18 to 19 years
    		 0 0 0
        20 to 29 years
    		 23 20 43
        30 to 39 years
    		 57 45 102
        40 to 49 years
    		 29 37 66
        50 to 55 years
    		 3 9 12
        > 55 years
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36 ( 7.46 ) 37.3 ( 8.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 84 78 162
        Male
    		 29 33 62

    End points

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    End points reporting groups
    Reporting group title
    Part I Placebo
    Reporting group description
    		 Subjects randomized to placebo BID began dosing at 1 placebo capsule orally BID for the first 7 days and escalated to 2 placebo capsules orally BID from Day 8 through Week 24 (end of Part I).

    Reporting group title
    Part I BG00012 240 mg BID
    Reporting group description
    		 Subjects randomized to BG00012 began dosing at 120 mg BG00012 (1 capsule orally BID) for the first 7 days and escalated to 240 mg BG00012 (2 capsules orally BID) from Day 8 through Week 24 (end of Part I).
    Reporting group title
    Part II: Placebo/BG00012 240 mg BID (Switchers):
    Reporting group description
    		 “PBO/BG12” – Subjects who received placebo in Part I before receiving BG00012 240 milligram (mg) BID in Part II for up to 4.5 years.

    Reporting group title
    Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Reporting group description
    		 “BG12/BG12” - Subjects who received BG00012 240 mg BID in Part I, continued receiving BG00012 in Part II for up to 4.5 years.

    Subject analysis set title
    ITT Population: Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT Population: subjects who were randomized to placebo and received at least 1 dose of study treatment.

    Subject analysis set title
    ITT Population: BG00012 240 mg BID
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT Population: subjects who were randomized to BG00012 and received at least 1 dose of study treatment.

    Primary: MRI: Total Number of New Gd-Enhancing Lesions From Scans at Week 12 to 24: Part I

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    End point title
    		 MRI: Total Number of New Gd-Enhancing Lesions From Scans at Week 12 to 24: Part I
    End point description
    The total number of new Gd-enhancing lesions from qualified MRI scans at Weeks 12, 16, 20, and 24, calculated as the sum of new Gd-enhancing lesions from these four scans. Gd-enhancing lesions are detected when Gd leaks into the perivascular space due to local breakdown of the blood-brain barrier, indicating the presence of active inflammation in periventricular lesions. The Intent-to-Treat (ITT) population was defined as all randomized subjects who received at least 1 dose of study treatment (BG00012 or placebo).
    End point type
    Primary
    End point timeframe
    Week 12 to Week 24
    End point values
    		 ITT Population: Placebo ITT Population: BG00012 240 mg BID
    Number of subjects analysed
    113
    111
    Units: lesions
        arithmetic mean (standard deviation)
    4.3 ( 8.2 )
    1.1 ( 5.46 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Percentage change, 95% CI and p-value for comparison between the active and placebo groups, based on negative binomial regression, adjusted for region (Japan/Non-Japan) and baseline number of Gd lesions.
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 lesion mean ratio
    Point estimate
    0.164
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.101
         upper limit
    		 0.266
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Percentage change, 95% CI and p-value for comparison between the active and placebo groups, based on negative binomial regression, adjusted for region (Japan/Non-Japan) and baseline number of Gd lesions.
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 negative binomial regression
    Parameter type
    		 percentage reduction (vs. placebo)
    Point estimate
    83.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 73.4
         upper limit
    		 89.9
    Statistical analysis title
    		 Sensitivity Analysis 1
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Sensitivity Analysis 2
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 see footnote
    Confidence interval
    Notes
    [1] - Based on exclusion of 1 subject with outlier values and subjects who tested positive for anti-aquaporin 4 (AQP4) antibody.
    Statistical analysis title
    		 Sensitivity Analysis 3
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 see footnote
    Confidence interval
    Notes
    [2] - Based on imputation with interpolation for missing values at a visit that has valid readings at the visits immediately prior and after the visit with the missing value.

    Primary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs): Part II

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    End point title
    		 Number of Subjects with Treatment-Emergent Adverse Events (TEAEs): Part II [3]
    End point description
    A treatment-emergent AE was defined as an AE that started or worsened on or after the date of the first dose of study treatment. The Safety population: analyses of the total BG00012 240 mg BID experience combined all data (Parts I and II) from subjects who received BG00012 in both Parts I and II with Part II only data from subjects who received BG00012 in Part II of the study after switching from placebo (in Part I).
    End point type
    Primary
    End point timeframe
    Up to 4.5 Years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Part II: Placebo/BG00012 240 mg BID (Switchers): Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Number of subjects analysed
    108
    105
    Units: subjects
        number (not applicable)
    99
    98
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment-Emergent Serious Adverse Events (SAEs): Part II

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    End point title
    		 Number of Subjects with Treatment-Emergent Serious Adverse Events (SAEs): Part II [4]
    End point description
    A SAE is any untoward medical occurrence that at any dose: results in death, in the view of the Investigator, places the subject at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or results in a congenital anomaly/birth defect. The Safety population: analyses of the total BG00012 240 mg BID experience combined all data (Parts I and II) from subjects who received BG00012 in both Parts I and II with Part II only data from subjects who received BG00012 in Part II of the study after switching from placebo (in Part I).
    End point type
    Primary
    End point timeframe
    Up to 4.5 Years
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Part II: Placebo/BG00012 240 mg BID (Switchers): Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Number of subjects analysed
    108
    105
    Units: subjects
        number (not applicable)
    28
    28
    No statistical analyses for this end point

    Primary: Number of Subjects with Clinically Significant Laboratory Values Reported as Adverse Events: Part II

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    End point title
    		 Number of Subjects with Clinically Significant Laboratory Values Reported as Adverse Events: Part II [5]
    End point description
    Clinical laboratory evaluations included haematology, blood chemistry, lipid profile, and urinalysis. The Safety population: analyses of the total BG00012 240 mg BID experience combined all data (Parts I and II) from subjects who received BG00012 in both Parts I and II with Part II only data from subjects who received BG00012 in Part II of the study after switching from placebo (in Part I).
    End point type
    Primary
    End point timeframe
    Up to 4.5 Years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Part II: Placebo/BG00012 240 mg BID (Switchers): Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Number of subjects analysed
    108
    105
    Units: subjects
    number (not applicable)
        LYMPHOCYTE COUNT DECREASED
    6
    9
        ALANINE AMINOTRANSFERASE INCREASED
    5
    8
        ASPARTATE AMINOTRANSFERASE INCREASED
    4
    5
        BLOOD GLUCOSE INCREASED
    0
    3
        GAMMA-GLUTAMYLTRANSFERASE INCREASED
    2
    3
        WHITE BLOOD CELL COUNT DECREASED
    4
    3
        BLOOD URIC ACID INCREASED
    0
    2
        BLOOD BILIRUBIN INCREASED
    0
    1
        BLOOD CHOLESTEROL INCREASED
    0
    1
        BLOOD TRIGLYCERIDES INCREASED
    0
    1
        HAEMATOCRIT DECREASED
    0
    1
        HAEMOGLOBIN DECREASED
    0
    1
        LIVER FUNCTION TEST ABNORMAL
    1
    1
        NEUTROPHIL COUNT DECREASED
    1
    1
        PROTEIN URINE
    1
    1
        WHITE BLOOD CELLS URINE POSITIVE
    0
    1
        BETA 2 MICROGLOBULIN INCREASED
    1
    0
        BLOOD ALKALINE PHOSPHATASE INCREASED
    1
    0
        BLOOD URINE PRESENT
    1
    0
        EOSINOPHIL COUNT INCREASED
    1
    0
        HEPATIC ENZYME INCREASED
    1
    0
        LOW DENSITY LIPOPROTEIN INCREASED
    1
    0
        MEAN CELL VOLUME INCREASED
    1
    0
        OCCULT BLOOD
    1
    0
        OCCULT BLOOD POSITIVE
    1
    0
        TRANSAMINASES INCREASED
    1
    0
        URINARY CASTS
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Clinically Significant Changes in Vital Signs: Part II

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    End point title
    		 Number of Subjects with Clinically Significant Changes in Vital Signs: Part II [6]
    End point description
    Vital signs were examined to determine the incidence of clinically relevant abnormalities and include diastolic and systolic blood pressure, heart rate, and temperature. The Safety population: analyses of the total BG00012 240 mg BID experience combined all data (Parts I and II) from subjects who received BG00012 in both Parts I and II with Part II only data from subjects who received BG00012 in Part II of the study after switching from placebo (in Part I).
    End point type
    Primary
    End point timeframe
    Up to 4.5 Years
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Part II: Placebo/BG00012 240 mg BID (Switchers): Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Number of subjects analysed
    108
    105
    Units: subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: MRI: Total Number of New Gd-Enhancing Lesions From Scans at Weeks 4 to 24: Part I

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    End point title
    		 MRI: Total Number of New Gd-Enhancing Lesions From Scans at Weeks 4 to 24: Part I
    End point description
    The cumulative number of new Gd-enhancing lesions over the six MRI scans in the placebo-controlled phase was calculated as the sum of the new Gd-enhancing lesions from the Week 4 to Week 24 scans. The ITT population was defined as all randomized subjects who received at least 1 dose of study treatment (BG00012 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 4 to Week 24
    End point values
    		 ITT Population: Placebo ITT Population: BG00012 240 mg BID
    Number of subjects analysed
    113
    111
    Units: lesions
        arithmetic mean (standard deviation)
    6.5 ( 10.7 )
    2.6 ( 12.57 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Percentage change, 95% CI and p-value for comparison between the active and placebo groups, based on negative binomial regression, adjusted for region (Japan/Non-Japan) and baseline number of Gd lesions.
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 lesion mean ratio
    Point estimate
    0.247
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.167
         upper limit
    		 0.366
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Percentage change, 95% CI and p-value for comparison between the active and placebo groups, based on negative binomial regression, adjusted for region (Japan/Non-Japan) and baseline number of Gd lesions.
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 negative binomial regression
    Parameter type
    		 percentage reduction (vs. placebo)
    Point estimate
    75.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 63.4
         upper limit
    		 83.3

    Secondary: MRI: Total Number of New or Newly Enlarging T2 Lesions at Week 24 Compared to Baseline: Part I

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    End point title
    		 MRI: Total Number of New or Newly Enlarging T2 Lesions at Week 24 Compared to Baseline: Part I
    End point description
    The total number of new or newly-enlarging T2 hyperintense lesions at Week 24 compared to baseline. Lesions detected on T2-weighted sequences have been shown to represent a range of histopathology related to MS, including edema, inflammation, demyelination, gliosis, and axon loss. The ITT population was defined as all randomized subjects who received at least 1 dose of study treatment (BG00012 or placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 ITT Population: Placebo ITT Population: BG00012 240 mg BID
    Number of subjects analysed
    113
    111
    Units: lesions
        arithmetic mean (standard deviation)
    4.9 ( 6.23 )
    1.9 ( 3.42 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Percentage change, 95% CI and p-value for comparison between the active and placebo groups, based on negative binomial regression, adjusted for region (Japan/Non-Japan) and baseline volume of T2 lesions.
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 lesion mean ratio
    Point estimate
    0.368
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.258
         upper limit
    		 0.525
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Percentage change, 95% CI and p-value for comparison between the active and placebo groups, based on negative binomial regression, adjusted for region (Japan/Non-Japan) and baseline volume of T2 lesions.
    Comparison groups
    ITT Population: Placebo v ITT Population: BG00012 240 mg BID
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 negative binomial regression
    Parameter type
    		 percentage reduction (vs. placebo)
    Point estimate
    63.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.5
         upper limit
    		 74.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study treatment to the End of Study (Up to 4.5 Years)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Part I Placebo
    Reporting group description
    		 Subjects randomized to placebo BID began dosing at 1 placebo capsule orally BID for the first 7 days and escalated to 2 placebo capsules orally BID from Day 8 through Week 24 (end of Part I).

    Reporting group title
    Part I BG00012 240 mg BID
    Reporting group description
    		 Subjects randomized to BG00012 began dosing at 120 mg BG00012 (1 capsule orally BID) for the first 7 days and escalated to 240 mg BG00012 (2 capsules orally BID) from Day 8 through Week 24 (end of Part I).

    Reporting group title
    Part II: Placebo/BG00012 240 mg BID (Switchers)
    Reporting group description
    		 “PBO/BG12” – Subjects who received placebo in Part I before receiving BG00012 240 milligram (mg) BID in Part II for up to 4.5 years.

    Reporting group title
    Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Reporting group description
    		 “BG12/BG12” - Subjects who received BG00012 240 mg BID in Part I, continued receiving BG00012 in Part II for up to 4.5 years.

    Serious adverse events
    		 Part I Placebo Part I BG00012 240 mg BID Part II: Placebo/BG00012 240 mg BID (Switchers) Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 113 (14.16%)
    13 / 111 (11.71%)
    28 / 108 (25.93%)
    28 / 105 (26.67%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fallopian tube cancer
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatoform disorder
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Protein urine
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug toxicity
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    3 / 105 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    16 / 113 (14.16%)
    10 / 111 (9.01%)
    18 / 108 (16.67%)
    16 / 105 (15.24%)
         occurrences causally related to treatment / all
    2 / 22
    1 / 15
    0 / 29
    1 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hypertonic bladder
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Microalbuminuria
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part I Placebo Part I BG00012 240 mg BID Part II: Placebo/BG00012 240 mg BID (Switchers) Part II: BG00012 240 mg BID/BG00012 240 mg BID (Continuers)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 113 (62.83%)
    85 / 111 (76.58%)
    95 / 108 (87.96%)
    91 / 105 (86.67%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 113 (0.88%)
    7 / 111 (6.31%)
    5 / 108 (4.63%)
    8 / 105 (7.62%)
         occurrences all number
    1
    8
    8
    16
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 111 (1.80%)
    6 / 108 (5.56%)
    9 / 105 (8.57%)
         occurrences all number
    0
    3
    7
    15
    Vascular disorders
    Flushing
         subjects affected / exposed
    10 / 113 (8.85%)
    26 / 111 (23.42%)
    38 / 108 (35.19%)
    3 / 105 (2.86%)
         occurrences all number
    12
    28
    85
    6
    Hot flush
         subjects affected / exposed
    1 / 113 (0.88%)
    7 / 111 (6.31%)
    4 / 108 (3.70%)
    4 / 105 (3.81%)
         occurrences all number
    1
    7
    4
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 113 (0.88%)
    3 / 111 (2.70%)
    3 / 108 (2.78%)
    6 / 105 (5.71%)
         occurrences all number
    1
    3
    5
    6
    Headache
         subjects affected / exposed
    2 / 113 (1.77%)
    4 / 111 (3.60%)
    12 / 108 (11.11%)
    12 / 105 (11.43%)
         occurrences all number
    4
    5
    13
    26
    Hypoaesthesia
         subjects affected / exposed
    0 / 113 (0.00%)
    3 / 111 (2.70%)
    4 / 108 (3.70%)
    6 / 105 (5.71%)
         occurrences all number
    0
    3
    6
    7
    Multiple sclerosis relapse
         subjects affected / exposed
    31 / 113 (27.43%)
    23 / 111 (20.72%)
    39 / 108 (36.11%)
    39 / 105 (37.14%)
         occurrences all number
    41
    31
    77
    79
    Paraesthesia
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 111 (1.80%)
    8 / 108 (7.41%)
    2 / 105 (1.90%)
         occurrences all number
    0
    2
    10
    2
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 111 (1.80%)
    7 / 108 (6.48%)
    6 / 105 (5.71%)
         occurrences all number
    0
    2
    10
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 111 (0.90%)
    5 / 108 (4.63%)
    6 / 105 (5.71%)
         occurrences all number
    2
    1
    5
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 113 (0.00%)
    8 / 111 (7.21%)
    8 / 108 (7.41%)
    0 / 105 (0.00%)
         occurrences all number
    0
    11
    8
    0
    Abdominal pain upper
         subjects affected / exposed
    6 / 113 (5.31%)
    5 / 111 (4.50%)
    16 / 108 (14.81%)
    2 / 105 (1.90%)
         occurrences all number
    8
    5
    22
    2
    Diarrhoea
         subjects affected / exposed
    6 / 113 (5.31%)
    11 / 111 (9.91%)
    15 / 108 (13.89%)
    6 / 105 (5.71%)
         occurrences all number
    6
    12
    20
    7
    Dyspepsia
         subjects affected / exposed
    3 / 113 (2.65%)
    2 / 111 (1.80%)
    7 / 108 (6.48%)
    4 / 105 (3.81%)
         occurrences all number
    3
    2
    8
    4
    Nausea
         subjects affected / exposed
    6 / 113 (5.31%)
    10 / 111 (9.01%)
    13 / 108 (12.04%)
    5 / 105 (4.76%)
         occurrences all number
    7
    10
    19
    7
    Vomiting
         subjects affected / exposed
    0 / 113 (0.00%)
    5 / 111 (4.50%)
    9 / 108 (8.33%)
    4 / 105 (3.81%)
         occurrences all number
    0
    6
    13
    4
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 111 (0.00%)
    6 / 108 (5.56%)
    6 / 105 (5.71%)
         occurrences all number
    2
    0
    6
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 113 (1.77%)
    8 / 111 (7.21%)
    10 / 108 (9.26%)
    6 / 105 (5.71%)
         occurrences all number
    7
    9
    12
    7
    Rash
         subjects affected / exposed
    0 / 113 (0.00%)
    3 / 111 (2.70%)
    3 / 108 (2.78%)
    10 / 105 (9.52%)
         occurrences all number
    0
    4
    4
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 113 (3.54%)
    3 / 111 (2.70%)
    6 / 108 (5.56%)
    6 / 105 (5.71%)
         occurrences all number
    4
    4
    6
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 113 (3.54%)
    1 / 111 (0.90%)
    9 / 108 (8.33%)
    15 / 105 (14.29%)
         occurrences all number
    6
    1
    10
    20
    Back pain
         subjects affected / exposed
    3 / 113 (2.65%)
    3 / 111 (2.70%)
    4 / 108 (3.70%)
    8 / 105 (7.62%)
         occurrences all number
    3
    3
    5
    10
    Pain in extremity
         subjects affected / exposed
    1 / 113 (0.88%)
    2 / 111 (1.80%)
    6 / 108 (5.56%)
    4 / 105 (3.81%)
         occurrences all number
    1
    2
    8
    4
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 111 (0.90%)
    7 / 108 (6.48%)
    8 / 105 (7.62%)
         occurrences all number
    0
    1
    9
    9
    Gastroenteritis
         subjects affected / exposed
    0 / 113 (0.00%)
    4 / 111 (3.60%)
    3 / 108 (2.78%)
    9 / 105 (8.57%)
         occurrences all number
    0
    4
    5
    9
    Herpes zoster
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 111 (0.00%)
    6 / 108 (5.56%)
    5 / 105 (4.76%)
         occurrences all number
    1
    0
    6
    7
    Influenza
         subjects affected / exposed
    1 / 113 (0.88%)
    2 / 111 (1.80%)
    6 / 108 (5.56%)
    18 / 105 (17.14%)
         occurrences all number
    1
    2
    8
    20
    Nasopharyngitis
         subjects affected / exposed
    28 / 113 (24.78%)
    25 / 111 (22.52%)
    41 / 108 (37.96%)
    47 / 105 (44.76%)
         occurrences all number
    45
    28
    123
    131
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 113 (9.73%)
    5 / 111 (4.50%)
    21 / 108 (19.44%)
    8 / 105 (7.62%)
         occurrences all number
    17
    7
    43
    17

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2012
    The primary reason for this amendment was to extend the contraception requirement from 30 days after the last dose of study treatment through the Final Safety Follow-Up Visit 12 weeks after the last dose of study treatment.
    22 Nov 2013
    The primary reasons for this amendment were to: - Open the study in the Czech Republic and Poland in addition to Japan, South Korea, and Taiwan. Although China was originally included, the study was withdrawn from China prior to study approval in that country. The title of the study was updated to reflect these changes. - Recommend that visits for female subjects be scheduled when the subject was not menstruating as a precaution against contamination of urine samples. - Anti-APQ4 antibody testing was to occur at the first Relapse Assessment Visit but was not required at any subsequent Relapse Assessment Visit. - Weight was added as an assessment at the End of Study/Premature Withdrawal/Final Safety Follow-Up Visit. - Clarify that MRI was not to be performed within 28 days after completing a course of steroids. - Clarify that if a subject had positive urinalysis test at Screening and the etiology was known (e.g., due to menses or urinary tract infection in the case of hematuria, or due to recent steroid use or elevated serum glucose in the case of glycosuria), a repeat test was not required.
    10 Dec 2014
    The primary reasons for this amendment were to: - Enable the early identification of subjects in Parts I or II who are at risk for developing severe, prolonged lymphopenia, and to provide additional guidance on the management of such subjects. In addition, lymphocyte and subset counts have been supplemented as an exploratory endpoint with the objective to study the impact of BG00012 treatment on lymphocytes and the recovery of lymphocyte count in patients with lymphopenia. - Extend the duration of study participation from 28 or 40 weeks to 28 to 52 weeks to reflect the additional safety follow-up for subjects with abnormally low lymphocyte counts. Subjects who completed Part I and did not enroll in Part II of the study or subjects who permanently discontinued study treatment for any reason and had a lymphocyte count <LLN were to be followed until the lymphocyte count was ≥LLN or until 24 weeks after the last dose (whichever was sooner). - Clarify that the use of alternative MS therapies was allowed only after the Investigators had contacted Biogen or its designee to determine their necessity in subjects who completed Part I and did not enroll in Part II of the study or subjects who permanently discontinued study treatment. - Country was added as a covariate for the statistical modelling of additional endpoints to be consistent with the analysis of the primary and secondary endpoints. - If lymphocyte count remains <500/mm3 for ≥24 weeks consecutively, study treatment will be permanently discontinued, and recovery of lymphocytes will be followed.

    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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