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    Clinical Trial Results:
    A Dose-Frequency Blinded, Multicenter, Extension Study to Determine the Long Term Safety and Efficacy of PEGylated Interferon Beta-1a (BIIB017) in Subjects with Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    2010-024477-39
    Trial protocol
    LV   BE   DE   ES   BG   EE   GB   GR   CZ  
    Global end of trial date
    02 Oct 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    29 Jan 2017
    First version publication date
    14 Oct 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Added minor description clarifications

    Trial information

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    Trial identification
    Sponsor protocol code
    105MS302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01332019
    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
    02 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety and tolerability of BIIB017 in subjects originally treated in Study 105MS301 who continued BIIB017 treatment. The secondary objective of this study was to describe the long-term MS outcomes in subjects originally treated in Study 105MS301 who continued BIIB017 treatment.
    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
    15 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Peru: 20
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Georgia: 16
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Estonia: 13
    Country: Number of subjects enrolled
    New Zealand: 12
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Poland: 312
    Country: Number of subjects enrolled
    Ukraine: 134
    Country: Number of subjects enrolled
    India: 108
    Country: Number of subjects enrolled
    Serbia: 104
    Country: Number of subjects enrolled
    Russian Federation: 89
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Germany: 27
    Worldwide total number of subjects
    1077
    EEA total number of subjects
    532
    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)
    1077
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study 105MS302 (NCT01332019) is an extension study and includes participants previously randomized to Study 105MS301 (NCT00906399). Only participants in Study 105MS301 who completed the study treatment and visit schedule through Week 96 were eligible for entry into this study.

    Pre-assignment
    Screening details
    Participants continued BIIB017 at the same dosage regimen they were following during treatment year 2 of Study 105MS301: BIIB017 125 μg subcutaneously (SC) every 2 weeks (Q2W) or every 4 weeks (Q4W). A major change in study design was introduced in Amendment 3 of the protocol, which switched all ongoing subjects dosing Q4W to dosing Q2W.

    Pre-assignment period milestones
    Number of subjects started
    1077
    Number of subjects completed
    1076

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Subject was not dosed: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Dose frequency (Q2W or Q4W) was blinded in this study, and the study was also rater-blinded (separate study personnel were assigned to conduct efficacy assessments and treat subjects) to protect against perceived dose-frequency unblinding of subjects’ treatment assignments. When Amendment 3 took effect, the study became open-label although the dose frequency was not unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BIIB017 Q4W
    Arm description
    125 µg BIIB017 administered by SC injection Q4W for at least 2 years and up to 4 years.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated Interferon Beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    Plegridy, PEG IFN β-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Study treatment was administered by SC self-injection into the skin. Subjects could inject study treatment into the thigh, abdomen, or arms.

    Arm title
    BIIB017 Q2W
    Arm description
    125 µg BIIB017 administered by SC injection Q2W for at least 2 years and up to 4 years.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated Interferon Beta-1a
    Investigational medicinal product code
    BIIB017
    Other name
    Plegridy, PEG IFN β-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Study treatment was administered by SC self-injection into the skin. Subjects could inject study treatment into the thigh, abdomen, or arms.

    Number of subjects in period 1 [1]
    BIIB017 Q4W BIIB017 Q2W
    Started
    529
    547
    Completed
    417
    425
    Not completed
    112
    122
         Physician decision
    4
    3
         NotSpecified
    16
    18
         Adverse event, serious fatal
    2
    1
         Adverse event, non-fatal
    13
    22
         Consent withdrawn by subject
    73
    71
         Lost to follow-up
    4
    7
    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: As shown in the "pre-assignment period milestones," 1077 subjects started in this study and 1 subject was not dosed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BIIB017 Q4W
    Reporting group description
    125 µg BIIB017 administered by SC injection Q4W for at least 2 years and up to 4 years.

    Reporting group title
    BIIB017 Q2W
    Reporting group description
    125 µg BIIB017 administered by SC injection Q2W for at least 2 years and up to 4 years.

    Reporting group values
    BIIB017 Q4W BIIB017 Q2W Total
    Number of subjects
    529 547 1076
    Age Categorical
    Units: Subjects
        20-29 years
    131 107 238
        30-39 years
    165 180 345
        40-49 years
    150 172 322
        50-59 years
    80 83 163
        60-65 years
    3 5 8
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    38.1 ± 9.95 38.7 ± 9.59 -
    Gender, Male/Female
    Units: Subjects
        Female
    378 397 775
        Male
    151 150 301

    End points

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    End points reporting groups
    Reporting group title
    BIIB017 Q4W
    Reporting group description
    125 µg BIIB017 administered by SC injection Q4W for at least 2 years and up to 4 years.

    Reporting group title
    BIIB017 Q2W
    Reporting group description
    125 µg BIIB017 administered by SC injection Q2W for at least 2 years and up to 4 years.

    Primary: Number of Participants Experiencing Adverse Events (AEs) Serious AEs, and Discontinuations Due to AEs

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    End point title
    Number of Participants Experiencing Adverse Events (AEs) Serious AEs, and Discontinuations Due to AEs [1]
    End point description
    AE: any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. SAE: any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, placed the subject at immediate risk of death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, could have jeopardized the subject or may have required intervention to prevent 1 of the other outcomes listed in the definition above. Data collected after Amendment 3 took effect were excluded for subjects enrolled into study 105MS302 on every 4 week dosing, but not excluded for subjects enrolled on every 2 week dosing. For subjects who switched to alternative MS medications, data after switch and 14 days after last dose of study treatment are excluded.
    End point type
    Primary
    End point timeframe
    up to 4 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented for this endpoint, per protocol.
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: participants
        Any event
    471
    478
        Moderate or severe event
    343
    348
        Severe event
    74
    73
        Event related to study treatment
    400
    399
        Serious event
    113
    90
        Discontinuing study treatment due to an event
    18
    26
        Withdrawing from study due to an event
    14
    23
    No statistical analyses for this end point

    Primary: Number of Participants With Potentially Clinically Significant Hematology Laboratory Abnormalities

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    End point title
    Number of Participants With Potentially Clinically Significant Hematology Laboratory Abnormalities [2]
    End point description
    Data collected after Amendment 3 took effect were excluded for subjects enrolled into study 105MS302 on every 4 week dosing, but not excluded for subjects enrolled on every 2 week dosing.
    End point type
    Primary
    End point timeframe
    up to 4 years
    Notes
    [2] - 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: Descriptive statistics are presented for this endpoint, per protocol.
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    528
    547
    Units: participants
        White blood cells < 3.0*10^9/L
    28
    86
        White blood cells ≥ 16.0*10^9/L
    13
    4
        Lymphocytes < 0.8*10^9/L
    41
    62
        Lymphocytes < 0.5*10^9/L
    2
    7
        Lymphocytes > 12*10^9/L
    0
    0
        Segmented neutrophils ≤ 1*10^9/L
    8
    16
        Segmented neutrophils < 1.5*10^9/L
    31
    84
        Segmented neutrophils ≥ 12*10^9/L
    18
    5
        Total absolute neutrophils ≤ 1*10^9/L
    8
    15
        Total absolute neutrophils < 1.5*10^9/L
    31
    83
        Total absolute neutrophils ≥ 12*10^9/L
    18
    5
        Red blood cells ≤ 3.3*10^12/L
    1
    7
        Red blood cells ≥ 6.8*10^12/L
    0
    0
        Hemoglobin ≤ 100 g/L
    33
    35
        Platelet count ≤ 100*10^9/L
    3
    11
        Platelet count ≥ 600*10^9/L
    2
    2
    No statistical analyses for this end point

    Primary: Number of Participants With Shifts From Baseline: Liver Function Laboratory Values

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    End point title
    Number of Participants With Shifts From Baseline: Liver Function Laboratory Values [3]
    End point description
    Shift to low includes normal to low, high to low, and unknown to low. Shift to high includes normal to high, low to high, and unknown to high. For participants who switched to alternative MS medications, data after switch and 14 days after last dose of study treatment are excluded. Data collected after Amendment 3 took effect were excluded for subjects enrolled into study 105MS302 on every 4 week dosing, but not excluded for subjects enrolled on every 2 week dosing. ALT=alanine aminotranferase; AST=aspartate aminotransferase; GGT=gamma-glutamyl transferase.
    End point type
    Primary
    End point timeframe
    Baseline (BIIB017 Treatment Baseline from Study 105MS301) up to 4 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: Descriptive statistics are presented for this endpoint, per protocol.
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: participants
        ALT: shift to low; n=528, 546
    3
    3
        ALT: shift to high; n=487, 497
    119
    153
        AST: shift to low; n=528, 546
    10
    8
        AST: shift to high; n=514, 530
    75
    110
        Total bilirubin: shift to low; n=512, 517
    94
    76
        Total bilirubin: shift to high; n=511, 535
    22
    16
        GGT: shift to low; n=529, 545
    16
    6
        GGT: shift to high; n=512, 528
    73
    97
        Alkaline phosphatase: shift to low; n=522, 543
    4
    5
        Alkaline phosphatase: shift to high; n=516, 536
    28
    26
        Lactate dehydrogenase: shift to low; n=529, 547
    0
    0
        Lactate dehydrogenase: shift to high; n=524, 541
    18
    30
    No statistical analyses for this end point

    Primary: Number of Participants With Shifts From Baseline: Kidney Function and Other Blood Chemistry

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    End point title
    Number of Participants With Shifts From Baseline: Kidney Function and Other Blood Chemistry [4]
    End point description
    Shift to low includes normal to low, high to low, and unknown to low. Shift to high includes normal to high, low to high, and unknown to high. For participants who switched to alternative MS medications, data after switch and 14 days after last dose of study treatment are excluded. Data collected after Amendment 3 took effect were excluded for subjects enrolled into Study 105MS302 on every 4 week dosing, but not excluded for subjects enrolled on every 2 week dosing. TSH=thyroid stimulating hormone.
    End point type
    Primary
    End point timeframe
    Baseline (BIIB017 Treatment Baseline from Study 105MS301) up to 4 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: Descriptive statistics are presented for this endpoint, per protocol.
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: participants
        Blood urea nitrogen: shift to low; n=529, 546
    0
    1
        Blood urea nitrogen: shift to high; n=527, 543
    16
    20
        Creatinine: shift to low; n=529, 547
    0
    1
        Creatinine: shift to high; n=528, 545
    15
    8
        Bicarbonate: shift to low; n=523, 540
    49
    64
        Bicarbonate: shift to high; n=529, 544
    0
    0
        Sodium: shift to low; n=529, 546
    0
    3
        Sodium: shift to high; n=524, 544
    39
    46
        Potassium: shift to low; n=527, 544
    13
    21
        Potassium: shift to high; n=528, 546
    17
    20
        Chloride: shift to low; n=529, 546
    1
    2
        Chloride: shift to high; n=528, 547
    0
    3
        Glucose: shift to low; n=522, 539
    54
    51
        Glucose: shift to high; n=506, 513
    304
    311
        TSH: shift to low; n=515, 533
    47
    30
        TSH: shift to high; n=518, 539
    37
    55
    No statistical analyses for this end point

    Primary: Number of Participants With Shifts From Baseline: Urinalysis

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    End point title
    Number of Participants With Shifts From Baseline: Urinalysis [5]
    End point description
    Shift to low includes normal to low, high to low, and unknown to low. Shift to high/positive includes normal to high/positive, low to high/positive, negative to high/positive, and unknown to high/positive. For participants who switched to alternative MS medications, data after switch and 14 days after last dose of study treatment are excluded. Data collected after Amendment 3 took effect were excluded for subjects enrolled into Study 105MS302 on every 4 week dosing, but not excluded for subjects enrolled on every 2 week dosing. Pos=positive; RBC=red blood cells; WBC=white blood cells.
    End point type
    Primary
    End point timeframe
    Baseline (BIIB017 Treatment Baseline from Study 105MS301) up to 4 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: Descriptive statistics are presented for this endpoint, per protocol.
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: participants
        Specific gravity: shift to low; n=525, 545
    2
    1
        Specific gravity: shift to high/pos; n=528,547
    13
    3
        pH: shift to low; n=529, 547
    0
    0
        pH: shift to high/pos; n=528, 547
    6
    4
        Color: shift to high/pos; n=516, 529
    33
    36
        Blood: shift to high/pos; n=469, 495
    159
    167
        Glucose: shift to high/pos; n=521, 542
    28
    25
        Ketones: shift to high/pos; n=510, 530
    64
    73
        Protein: shift to high/pos; n=380, 391
    270
    277
        RBC: shift to high/pos; n=419, 402
    110
    106
        WBC: shift to high/pos; n=472, 495
    116
    130
        Bilirubin: shift to high/pos; n=529, 547
    0
    1
        Nitrite: shift to high/pos; n=508, 519
    84
    94
        Urobilinogen: shift to high/pos; n=529, 546
    7
    13
    No statistical analyses for this end point

    Secondary: Annualized Relapse Rate (ARR)

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    End point title
    Annualized Relapse Rate (ARR)
    End point description
    Relapses are defined as new or recurrent neurologic 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. The annualized relapse rate is calculated as the total number of relapses occurred during the period for all subjects, divided by the total number of subject-years followed in the period.
    End point type
    Secondary
    End point timeframe
    up to 4 years
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: relapses per person-years
        number (confidence interval 95%)
    0.189 (0.154 to 0.231)
    0.142 (0.114 to 0.177)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on negative binomial regression for each treatment group, with adjustment for EDSS (<4 vs. >=4), relapse rate (based on 1 year before 105MS301 and 105MS301), and age (<40 vs. >=40) at 105MS302 baseline.
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0203 [6]
    Method
    negative binomial regression
    Parameter type
    rate ratio
    Point estimate
    0.755
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.595
         upper limit
    0.957
    Notes
    [6] - q2w/q4w

    Secondary: Percentage of Participants Who Relapsed

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    End point title
    Percentage of Participants Who Relapsed
    End point description
    Relapses are defined as new or recurrent neurologic 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. New or recurrent neurologic symptoms that occur less than 30 days following the onset of a relapse were considered part of the same relapse. Participants who did not experience a relapse prior to switching to alternative MS medications, withdrew from study, or Amendment 3 (A3) took effect were censored at the time of switch/withdrawal/A3 effective date.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: percentage of participants
        Did not relapse
    71
    77
        Relapsed
    29
    23
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    q2w/q4w
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0201 [7]
    Method
    Cox proportion hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    0.96
    Notes
    [7] - Based on Cox proportion hazards model, adjusted for EDSS (<4 vs >= 4), age (<40 vs >=40), relapse rate (based on 1 year before 105MS301 and 105MS301), and gadolinium (Gd) enhancing lesions (presence vs. absence) at 105MS302 baseline.

    Secondary: Number of New or Newly Enlarging T2 Hyperintense Lesions

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    End point title
    Number of New or Newly Enlarging T2 Hyperintense Lesions
    End point description
    The total number of new or newly enlarging T2 hyperintense lesions (from Study 105MS302 Baseline) as assessed by magnetic resonance imaging (MRI). Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    481
    493
    Units: lesions
    arithmetic mean (standard deviation)
        Week 48; n=481, 493
    4.4 ± 8.19
    1.9 ± 4.5
        Week 96; n=411, 407
    8.9 ± 16.64
    3.9 ± 9.37
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 48
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    negative binomial regression
    Parameter type
    lesion mean ratio
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    0.63
    Notes
    [8] - Lesion mean ratio (95% CI) and p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on negative binomial regression, adjusted for 105MS302 baseline number of T2 lesions.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 96
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    negative binomial regression
    Parameter type
    lesion mean ratio
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.62
    Notes
    [9] - Lesion mean ratio (95% CI) and p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on negative binomial regression, adjusted for 302 baseline number of T2 lesions.

    Secondary: Number of New Active Lesions

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    End point title
    Number of New Active Lesions
    End point description
    The number of new active lesions as assessed by MRI. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: lesions
    arithmetic mean (standard deviation)
        Week 48; n=481, 493
    4.4 ± 8.25
    2 ± 4.62
        Week 96; n=411, 406
    9 ± 16.88
    3.9 ± 9.47
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 48
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    negative binomial regression
    Parameter type
    lesion mean ratio
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    0.68
    Notes
    [10] - Lesion mean ratio (95% CI) and p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on negative binomial regression, adjusted for 105MS302 baseline number of Gd lesions.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 96
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    negative binomial regression
    Parameter type
    lesion mean ratio
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    0.71
    Notes
    [11] - Lesion mean ratio (95% CI) and p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on negative binomial regression, adjusted for 105MS302 baseline number of Gd lesions.

    Secondary: Number of New T1 Hypointense Lesions

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    End point title
    Number of New T1 Hypointense Lesions
    End point description
    The total number of new T1 hypointense lesions as assessed by MRI.
    End point type
    Secondary
    End point timeframe
    Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: lesions
    arithmetic mean (standard deviation)
        Week 48; n=481, 493
    1.4 ± 3.02
    0.8 ± 2.18
        Week 96; n=411, 406
    2.8 ± 5.92
    1.5 ± 4.14
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 48
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [12] - p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on multiple logit regression, adjusted for 302 baseline number of T1 lesions.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 96
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [13] - p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on multiple logit regression, adjusted for 302 baseline number of T1 lesions.

    Secondary: Number of Gd-Enhancing Lesions

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    End point title
    Number of Gd-Enhancing Lesions
    End point description
    The number of Gd-enhancing lesions as assessed by MRI. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: lesions
    arithmetic mean (standard deviation)
        Baseline; n=528, 543
    0.6 ± 1.85
    0.2 ± 1.07
        Week 48; n=481, 493
    0.7 ± 2.07
    0.2 ± 1.42
        Week 96; n=411, 407
    0.8 ± 2.59
    0.2 ± 0.89
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 96
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0026 [14]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [14] - p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on multiple logit regression, adjusted for 302 baseline number of Gd-enhancing lesion.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 48
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [15]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [15] - p-value for comparison between the every 2 weeks group and the every 4 weeks group, based on multiple logit regression, adjusted for 302 baseline number of Gd-enhancing lesion.

    Secondary: Volume of T2 Hyperintense Lesions

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    End point title
    Volume of T2 Hyperintense Lesions
    End point description
    The volume of T2 hyperintense lesions as assessed by MRI. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: cm^3
    arithmetic mean (standard deviation)
        Baseline; n=528, 543
    11.4742 ± 13.55811
    9.9678 ± 11.41807
        Week 48; n=481, 493
    11.7421 ± 13.91774
    9.8335 ± 11.05029
        Week 96; n=411, 407
    12.0257 ± 13.91056
    9.9487 ± 10.97208
    No statistical analyses for this end point

    Secondary: Volume of T1 Hypointense Lesions

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    End point title
    Volume of T1 Hypointense Lesions
    End point description
    The volume of T1 hypointense lesions as assessed by MRI. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: cm^3
    arithmetic mean (standard deviation)
        Baseline; n=528, 543
    3.9869 ± 6.29557
    3.632 ± 5.47465
        Week 48; n=481, 493
    4.3062 ± 6.92839
    3.6529 ± 5.19027
        Week 96; n=411, 407
    4.3171 ± 6.70107
    3.7494 ± 5.21314
    No statistical analyses for this end point

    Secondary: Volume of Gd-Enhancing Lesions

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    End point title
    Volume of Gd-Enhancing Lesions
    End point description
    The volume of Gd-enhancing lesions as assessed by MRI. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: cm^3
    arithmetic mean (standard deviation)
        Baseline; n=528, 543
    0.0911 ± 0.30013
    0.0348 ± 0.17344
        Week 48; n=481, 493
    0.1172 ± 0.42762
    0.0477 ± 0.31479
        Week 96; n=411, 407
    0.1346 ± 0.5058
    0.0357 ± 0.14976
    No statistical analyses for this end point

    Secondary: Percentage Change of Whole Brain Volume

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    End point title
    Percentage Change of Whole Brain Volume
    End point description
    Percentage change of whole brain volume as assessed by MRI. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Week 48, Week 96
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: percentage change
    arithmetic mean (standard deviation)
        Change at Week 48; n=402, 418
    -0.522 ± 0.6205
    -0.453 ± 0.8127
        Change at Week 96; n=365, 358
    -0.835 ± 1.0785
    -0.788 ± 1.1912
    No statistical analyses for this end point

    Secondary: Change from Baseline in Expanded Disability Status Scale (EDSS)

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    End point title
    Change from Baseline in Expanded Disability Status Scale (EDSS)
    End point description
    Change from Baseline in disability as measured by the Expanded Disability Status Scale (EDSS). The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 12, 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=516, 535
    2.43 ± 1.346
    2.35 ± 1.299
        Change at Week 12; n=503, 524
    0.02 ± 0.388
    0 ± 0.45
        Change at Week 24; n=500, 519
    0.02 ± 0.449
    0 ± 0.486
        Change at Week 48; n=488, 497
    0.08 ± 0.564
    0.03 ± 0.51
        Change at Week 72; n=468, 484
    0.13 ± 0.629
    0.06 ± 0.484
        Change at Week 96; n=429, 446
    0.15 ± 0.618
    0.09 ± 0.563
        Change at Week 120; n=187, 205
    0.19 ± 0.7
    0.1 ± 0.538
        Change at Week 144; n=90, 98
    0.23 ± 0.72
    0.1 ± 0.587
        Change at Week 168; n=21, 25
    0.24 ± 0.889
    0.18 ± 0.454
    No statistical analyses for this end point

    Secondary: Time to Sustained Disability Progression

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    End point title
    Time to Sustained Disability Progression
    End point description
    Estimated proportion of participants with progression and time to progression based on the Kaplan-Meier product limit method. Sustained disability progression is defined as: at least a 1.0 point increase on the EDSS from baseline EDSS ≥ 1.0 that is sustained for 24 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Participants were censored at the time of withdrawal/switch/A3 effective date if they withdrew from study, switched to alternative MS medication, or Amendment 3 took effect without a progression.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 28, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    63 [16]
    38 [17]
    Units: proportion of participants
    number (not applicable)
        Progressed at 12 weeks
    0.023
    0.007
        Progressed at 24 weeks
    0.046
    0.023
        Progressed at 48 weeks
    0.079
    0.045
        Progressed at 72 weeks
    0.103
    0.057
        Progressed at 96 weeks
    0.115
    0.069
        Progressed at 120 weeks
    0.147
    0.085
        Progressed at 144 weeks
    0.161
    0.096
        Progressed at 168 weeks
    99999
    99999
    Notes
    [16] - Subjects who experienced disability progression. 99999=was not calculated (under 30 subjects).
    [17] - Subjects who experienced disability progression. 99999=was not calculated (under 30 subjects).
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BIIB017 Q4W v BIIB017 Q2W
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006 [18]
    Method
    Cox Proportional Hazards model
    Parameter type
    Cox proportional hazard
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    0.85
    Notes
    [18] - Based on Cox Proportional Hazards model, adjusted for 105MS302 baseline EDSS and age (<40 vs >=40).

    Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT)

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    End point title
    Change From Baseline in Symbol Digit Modalities Test (SDMT)
    End point description
    SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 (worst) to 110 (best).
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=523, 543
    52.134 ± 17.7653
    52.744 ± 17.6994
        Change at Week 24; n=508, 530
    -0.313 ± 8.5862
    -1.106 ± 8.1292
        Change at Week 48; n=493, 509
    -0.365 ± 9.3557
    -0.864 ± 8.6059
        Change at Week 72; n=472, 489
    -0.625 ± 8.8037
    -1.012 ± 8.5038
        Change at Week 96; n=435, 450
    -0.34 ± 8.7817
    -0.231 ± 9.3148
        Change at Week 120; n=190, 203
    -1.305 ± 8.9248
    -1.099 ± 9.5425
        Change at Week 144; n=88, 96
    -1.727 ± 7.79
    -0.906 ± 10.8367
        Change at Week 168; n=21, 25
    -4 ± 10.4403
    -3.84 ± 13.4712
    No statistical analyses for this end point

    Secondary: Change from Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Score

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    End point title
    Change from Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Score
    End point description
    The 29-item MSIS-29 is a disease-specific participant-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 20 physical items and 9 psychological items. Responses use a 5-point Likert scale range from 1 to 5. All questions are to be answered. The physical well being assessment portion of the MSIS-29 consists of 20 questions in which subjects rate the impact of MS on their day-to-day life during the past two weeks from 1=no impact to 5=extreme impact for a total score of 20-100. A lower total score indicates less physically-related impact while a higher total score indicates greater physically-related impact on a participant's functioning. Observed data after subjects switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=527, 544
    20.494 ± 19.829
    20.218 ± 19.0264
        Change at Week 24; n=513, 534
    -0.152 ± 9.3332
    0.552 ± 10.0147
        Change at Week 48; n=498, 510
    0.462 ± 10.7054
    0.545 ± 10.6342
        Change at Week 72; n=474, 491
    0.937 ± 11.5682
    0.684 ± 12.469
        Change at Week 96; n=437, 452
    1.471 ± 10.8997
    1.19 ± 11.4005
        Change at Week 120; n=193, 205
    2.654 ± 14.2983
    0.116 ± 10.4382
        Change at Week 144; n=88, 98
    0.327 ± 10.5888
    0.051 ± 12.1417
        Change at Week 168; n=20, 26
    2.25 ± 7.3292
    -0.288 ± 13.5615
    No statistical analyses for this end point

    Secondary: Change from Baseline in 12-Item Short Form Health Survey (SF-12) Mental Component Scale (MCS)

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    End point title
    Change from Baseline in 12-Item Short Form Health Survey (SF-12) Mental Component Scale (MCS)
    End point description
    The SF-12 is a multipurpose short form survey with 12 questions, all selected from the SF-36 Health Survey. The questions were combined, scored, and weighted to create two scales that provide glimpses into mental and physical functioning and overall health-related-quality of life. MCS computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health and 100 indicates the highest level of health. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are exclu
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=527, 544
    47.803 ± 10.2111
    48.591 ± 10.3624
        Change at Week 24; n=514, 535
    0.396 ± 7.5967
    -0.734 ± 8.3567
        Change at Week 48; n=498, 510
    0.409 ± 8.4442
    -0.69 ± 8.3903
        Change at Week 72; n=474, 491
    0.242 ± 9.3223
    -0.162 ± 9.0676
        Change at Week 96; n=437, 452
    -0.141 ± 9.4833
    0.014 ± 8.8856
        Change at Week 120; n=193, 205
    -1.223 ± 10.4664
    0.616 ± 7.5313
        Change at Week 144; n=88, 98
    0.346 ± 8.6814
    0.11 ± 8.0301
        Change at Week 168; n=20, 26
    -0.451 ± 8.8575
    0.294 ± 9.7505
    No statistical analyses for this end point

    Secondary: Change from Baseline in SF-12 Physical Component Score (PCS)

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    End point title
    Change from Baseline in SF-12 Physical Component Score (PCS)
    End point description
    The SF-12 is a multipurpose short form survey with 12 questions, all selected from the SF-36 Health Survey. The questions were combined, scored, and weighted to create two scales that provide glimpses into mental and physical functioning and overall health-related-quality of life. PCS was computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health and 100 indicates the highest level of health. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        105MS302 Baseline; n=527, 544
    45.154 ± 9.4474
    44.902 ± 9.9312
        Change at Week 24; n=514, 535
    0.138 ± 6.0841
    0.337 ± 5.7878
        Change at Week 48; n=498, 510
    -0.351 ± 6.1785
    0.214 ± 5.8377
        Change at Week 72; n=474, 491
    -0.27 ± 6.6319
    -0.169 ± 6.3824
        Change at Week 96; n=437, 452
    -0.15 ± 6.6971
    -0.138 ± 6.4453
        Change at Week 120; n=193, 205
    -0.118 ± 7.8826
    0.021 ± 6.1354
        Change at Week 144; n=88, 98
    -0.256 ± 5.7252
    0.118 ± 6.783
        Change at Week 168; n=20, 26
    -1.558 ± 7.6525
    0.152 ± 7.5206
    No statistical analyses for this end point

    Secondary: Change form Baseline in Euro Quality of Life (EQ-5D) Index Score

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    End point title
    Change form Baseline in Euro Quality of Life (EQ-5D) Index Score
    End point description
    The EQ-5D is a participant-answered questionnaire scoring 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Scores of 1, 2, or 3 are possible responses for each of 5 questions (1=no problems, 2=some problems, 3=severe problems). A scoring formula developed by the EuroQol Group is then used to assign utility values for each participant’s Health State Profile. A summary index score (EQ-5D index score) is derived from the 5 questions by conversion with this scoring formula and a table of scores. EQ-5D Summary Index values ranged from -0.6 (worst health state) to 1.00 (perfect health state). Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=527, 544
    0.76 ± 0.23
    0.76 ± 0.23
        Change at Week 24; n=514, 534
    0 ± 0.159
    0 ± 0.171
        Change at Week 48; n=498, 510
    -0.01 ± 0.159
    0 ± 0.171
        Change at Week 72; n=472, 491
    -0.01 ± 0.158
    0 ± 0.179
        Change at Week 96; n=436, 452
    -0.01 ± 0.156
    -0.01 ± 0.195
        Change at Week 120; n=193, 205
    -0.02 ± 0.19
    0 ± 0.165
        Change at Week 144; n=88, 98
    0 ± 0.169
    0.01 ± 0.166
        Change at Week 168; n=21, 26
    0 ± 0.08
    0.02 ± 0.137
    No statistical analyses for this end point

    Secondary: Change Form Baseline in EQ-5D Visual Analogue Scale (VAS)

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    End point title
    Change Form Baseline in EQ-5D Visual Analogue Scale (VAS)
    End point description
    The EQ-5D VAS records the participant's self-rated health on a scale from 0-100 where 100 is the 'best imaginable health state' and 0 is the 'worst imaginable health state.' The scale was normalized to a scale of 0 to 1, with higher values indicating a better health state. Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Baseline (start of 105MS302), Weeks 24, 48, 72, 96, 120, 144, 168
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=527, 542
    77.07 ± 17.623
    77.33 ± 18.348
        Change at Week 24; n=511, 532
    -0.22 ± 11.411
    -0.98 ± 12.064
        Change at Week 48; n=498, 508
    -0.81 ± 12.828
    -0.93 ± 12.719
        Change at Week 72; n=472, 490
    -0.59 ± 12.735
    -1.89 ± 15.27
        Change at Week 96; n=436, 450
    -1.1 ± 14.266
    -2.2 ± 14.095
        Change at Week 120; n=193, 204
    -0.47 ± 12.714
    -0.88 ± 12.793
        Change at Week 144; n=88, 97
    -0.31 ± 14.247
    -0.87 ± 14.865
        Change at Week 168; n=21, 26
    1.38 ± 14.925
    0.46 ± 12.602
    No statistical analyses for this end point

    Secondary: Number of Relapses Requiring Intravenous (IV) Steroid Use

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    End point title
    Number of Relapses Requiring Intravenous (IV) Steroid Use
    End point description
    Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    up to 4 years
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: relapses
    217
    181
    No statistical analyses for this end point

    Secondary: Number of MS-Related Hospitalizations

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    End point title
    Number of MS-Related Hospitalizations
    End point description
    Observed data after participants switched to alternative MS medications or after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    up to 4 years
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529
    547
    Units: hospitalizations
    113
    81
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: How Tolerable or Intolerable Do You Find the Medication?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: How Tolerable or Intolerable Do You Find the Medication?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "How tolerable or intolerable do you find the medication?" answers were numerically rated from 1 (extremely intolerable) to 10 (extremely tolerable). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [19]
    547 [20]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    6.8 ± 2.36
    7 ± 2.21
        Year 2; n=425, 430
    7.2 ± 2.28
    7.1 ± 2.27
        Year 3; n=82, 88
    7.5 ± 2.46
    7.3 ± 2.17
    Notes
    [19] - n=subjects with an assessment at given timepoint.
    [20] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: How Convenient or Inconvenient Is It to Take Your Medication as Instructed?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: How Convenient or Inconvenient Is It to Take Your Medication as Instructed?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "How convenient or inconvenient is it to take your medication as instructed?" answers were numerically rated from 1 (extremely inconvenient) to 10 (extremely convenient). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [21]
    547 [22]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.2 ± 2.09
    8 ± 2.12
        Year 2; n=426, 430
    8.3 ± 1.98
    8.2 ± 2.05
        Year 3; n=82, 88
    8.3 ± 2.05
    8 ± 2.08
    Notes
    [21] - n=subjects with an assessment at given timepoint.
    [22] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: How Convenient or Inconvenient Is It to Take Your Medication Every 2 Weeks?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: How Convenient or Inconvenient Is It to Take Your Medication Every 2 Weeks?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "How convenient or inconvenient is it to take your medication every 2 weeks?" answers were numerically rated from 1 (extremely inconvenient) to 10 (extremely convenient). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [23]
    547 [24]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.4 ± 2.02
    8.4 ± 1.99
        Year 2; n=426, 430
    8.6 ± 1.93
    8.4 ± 2.06
        Year 3; n=82, 88
    8.6 ± 2
    8.5 ± 1.79
    Notes
    [23] - n=subjects with an assessment at given timepoint.
    [24] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: Overall, How Satisfied or Dissatisfied Are You With This Medication?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: Overall, How Satisfied or Dissatisfied Are You With This Medication?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "Overall, how satisfied or dissatisfied are you with this medication?" answers were numerically rated from 1 (extremely dissatisfied) to 10 (extremely satisfied). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [25]
    547 [26]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    7.9 ± 2.04
    8.1 ± 1.97
        Year 2; n=426, 430
    8.2 ± 2.04
    8.3 ± 2
        Year 3; n=82, 88
    8.2 ± 2
    8.6 ± 1.6
    Notes
    [25] - n=subjects with an assessment at given timepoint.
    [26] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: How Satisfied or Dissatisfied Are You With the Injection Frequency (Every 2 Weeks)?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: How Satisfied or Dissatisfied Are You With the Injection Frequency (Every 2 Weeks)?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "How satisfied or dissatisfied are you with the injection frequency (every 2 weeks)?" answers were numerically rated from 1 (extremely dissatisfied) to 10 (extremely satisfied). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [27]
    547 [28]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.4 ± 1.92
    8.3 ± 1.98
        Year 2; n=426, 430
    8.5 ± 1.89
    8.3 ± 2.07
        Year 3; n=82, 88
    8.7 ± 1.99
    8.6 ± 1.59
    Notes
    [27] - n=subjects with an assessment at given timepoint.
    [28] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: How Likely Would You Be to Continue to Use This Medication?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: How Likely Would You Be to Continue to Use This Medication?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "How likely would you be to continue to use this medication?" answers were numerically rated from 1 (extremely unlikely) to 10 (extremely likely). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [29]
    547 [30]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.5 ± 2.11
    8.6 ± 2
        Year 2; n=426, 430
    8.1 ± 2.67
    8.3 ± 2.58
        Year 3; n=82, 88
    8.5 ± 2.39
    8.8 ± 2
    Notes
    [29] - n=subjects with an assessment at given timepoint.
    [30] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: This Medication Enables Me to Focus More on Myself and My Family Rather Than My MS.

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: This Medication Enables Me to Focus More on Myself and My Family Rather Than My MS.
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the statement "This Medication Enables Me to Focus More on Myself and My Family Rather Than My MS," answers were numerically rated from 1 (strongly disagree) to 10 (strongly agree). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [31]
    547 [32]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    7.3 ± 2.52
    7.8 ± 2.21
        Year 2; n=426, 430
    7.8 ± 2.35
    7.8 ± 2.31
        Year 3; n=82, 88
    8 ± 2.44
    8.3 ± 2
    Notes
    [31] - n=subjects with an assessment at given timepoint.
    [32] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: This Medication Makes It Easy For Me to Carry Out My Daily Responsibilities.

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: This Medication Makes It Easy For Me to Carry Out My Daily Responsibilities.
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the statement "This medication makes it easy for me to carry out my daily responsibilities (ie, going to work, doing household chores or caring for my family)," answers were numerically rated from 1 (strongly disagree) to 10 (strongly agree). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [33]
    547 [34]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    7.4 ± 2.44
    7.7 ± 2.33
        Year 2; n=426, 429
    7.8 ± 2.32
    7.7 ± 2.35
        Year 3; n=82, 88
    7.9 ± 2.57
    8.3 ± 2.07
    Notes
    [33] - n=subjects with an assessment at given timepoint.
    [34] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: The Twice a Month Dosing Makes It More Convenient for Me to Travel/Vacation.

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: The Twice a Month Dosing Makes It More Convenient for Me to Travel/Vacation.
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the statement "The twice a month dosing makes it more convenient for me to travel/vacation," answers were numerically rated from 1 (strongly disagree) to 10 (strongly agree). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [35]
    547 [36]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.2 ± 2.21
    8.2 ± 2.13
        Year 2; n=426, 430
    8.3 ± 2.2
    8.2 ± 2.21
        Year 3; n=82, 88
    8.6 ± 1.97
    8.5 ± 1.86
    Notes
    [35] - n=subjects with an assessment at given timepoint.
    [36] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: The Twice a Month Dosing Enables Me to Be More Spontaneous and Flexible.

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: The Twice a Month Dosing Enables Me to Be More Spontaneous and Flexible.
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the statement "The twice a month dosing enables me to be more spontaneous and flexible," answers were numerically rated from 1 (strongly disagree) to 10 (strongly agree). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [37]
    547 [38]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.1 ± 2.2
    8.2 ± 2.09
        Year 2; n=426, 430
    8.3 ± 2.12
    8.2 ± 2.12
        Year 3; n=82, 88
    8.5 ± 2.17
    8.4 ± 1.93
    Notes
    [37] - n=subjects with an assessment at given timepoint.
    [38] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: This Medication Improves My Self-Confidence and Self-Reliance.

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: This Medication Improves My Self-Confidence and Self-Reliance.
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the statement "This medication improves my self-confidence and self-reliance," answers were numerically rated from 1 (strongly disagree) to 10 (strongly agree). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [39]
    547 [40]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    7.5 ± 2.47
    7.7 ± 2.29
        Year 2; n=426, 429
    7.9 ± 2.5
    7.9 ± 2.31
        Year 3; n=82, 88
    8.1 ± 2.45
    8.4 ± 1.98
    Notes
    [39] - n=subjects with an assessment at given timepoint.
    [40] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: I Am Satisfied With the Dosing Frequency of This Medication.

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: I Am Satisfied With the Dosing Frequency of This Medication.
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the statement "I am satisfied with the dosing frequency (2 times per month) of this medication" answers were numerically rated from 1 (strongly disagree) to 10 (strongly agree). Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [41]
    547 [42]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Year 1; n=482, 496
    8.4 ± 1.98
    8.5 ± 1.94
        Year 2; n=425, 430
    8.7 ± 1.83
    8.5 ± 2.06
        Year 3; n=82, 88
    8.8 ± 1.87
    8.7 ± 1.81
    Notes
    [41] - n=subjects with an assessment at given timepoint.
    [42] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: Over the Past 4 Weeks, Did You Miss Any of Your Injections?

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: Over the Past 4 Weeks, Did You Miss Any of Your Injections?
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "Over the past 4 weeks, did you miss any of your injections?" answer choices were given as "none missed," "miss 1 injection," or "miss 2 injections." Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [43]
    547 [44]
    Units: subjects
        Year 1: none missed; n=482, 493
    474
    487
        Year 1: 1 missed; n=482, 493
    8
    4
        Year 1: 2 missed; n=482, 493
    0
    2
        Year 2: none missed; n=426, 429
    422
    426
        Year 2: 1 missed; n=426, 429
    3
    2
        Year 2: 2 missed; n=426, 429
    1
    1
        Year 3: none missed; n=81, 88
    79
    86
        Year 3: 1 missed; n=81, 88
    0
    1
        Year 3: 2 missed; n=81, 88
    2
    1
    Notes
    [43] - n=subjects with an assessment at given timepoint.
    [44] - n=subjects with an assessment at given timepoint.
    No statistical analyses for this end point

    Secondary: Summary of Subject-Reported Treatment Satisfaction: Main Reason for Missed Injections

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    End point title
    Summary of Subject-Reported Treatment Satisfaction: Main Reason for Missed Injections
    End point description
    Subjects completed a Treatment Satisfaction Questionnaire composed of a range of 14 questions regarding the subject’s perception of treatment satisfaction at the end of each year of treatment. For the question "Main reason for missed injections?" answer choices were given as "medication side effects," "injection pain," "forget to take medication," "tired of taking injections," "don't think medication is working," or "other." Data after Amendment 3 took effect are excluded.
    End point type
    Secondary
    End point timeframe
    Year 1, Year 2, Year 3
    End point values
    BIIB017 Q4W BIIB017 Q2W
    Number of subjects analysed
    529 [45]
    547 [46]
    Units: subjects
        Year 1: medication side effects; n=8, 6
    0
    1
        Year 1: injection pain; n=8, 6
    0
    0
        Year 1: forget to take medication; n=8, 6
    2
    1
        Year 1: tired of taking injections; n=8, 6
    0
    0
        Year 1: don't think medication is working; n=8, 6
    0
    0
        Year 1: other; n=8, 6
    6
    4
        Year 2: medication side effects; n=4, 3
    1
    1
        Year 2: injection pain; n=4, 3
    0
    0
        Year 2: forget to take medication; n=4, 3
    1
    1
        Year 2: tired of taking injections; n=4, 3
    0
    0
        Year 2: don't think medication is working; n=4, 3
    0
    0
        Year 2: other; n=4, 3
    2
    1
        Year 3: medication side effects; n=3, 2
    0
    0
        Year 3: injection pain; n=3, 2
    0
    0
        Year 3: forget to take medication; n=3, 2
    0
    0
        Year 3: tired of taking injections; n=3, 2
    1
    1
        Year 3: don't think medication is working; n=3, 2
    0
    0
        Year 3: other; n=3, 2
    2
    1
    Notes
    [45] - n=subjects with an assessment who missed at least 1 injection at given timepoint.
    [46] - n=subjects with an assessment who missed at least 1 injection at given timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 4 years
    Adverse event reporting additional description
    All treatment-emergent events are presented. (An event was considered to be treatment emergent if it had an onset date on or after the date of first study treatment or if it was present prior to start of study treatment and subsequently worsened.)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    BIIB017 Q2W
    Reporting group description
    125 µg BIIB017 administered by SC injection Q2W for at least 2 years and up to 4 years.

    Reporting group title
    BIIB017 Q4W
    Reporting group description
    125 µg BIIB017 administered by SC injection Q4W for at least 2 years and up to 4 years.

    Serious adverse events
    BIIB017 Q2W BIIB017 Q4W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    91 / 547 (16.64%)
    114 / 529 (21.55%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         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)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangioma
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 547 (0.37%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar 1 disorder
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catatonia
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 547 (0.18%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    2 / 547 (0.37%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (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 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         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
    0 / 547 (0.00%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thermal burn
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         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
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 547 (0.18%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve prolapse
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 547 (0.00%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    3 / 547 (0.55%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial neuralgia
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 547 (0.37%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    57 / 547 (10.42%)
    83 / 529 (15.69%)
         occurrences causally related to treatment / all
    1 / 86
    1 / 117
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    2 / 547 (0.37%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary progressive multiple sclerosis
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 547 (0.37%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Heterophoria
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 547 (0.18%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 547 (0.18%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (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
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 547 (0.37%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 547 (0.18%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone cyst
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (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 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 547 (0.18%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basedow's disease
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         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
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious thyroiditis
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 547 (0.00%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         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 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 547 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 547 (0.18%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 547 (0.18%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BIIB017 Q2W BIIB017 Q4W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    438 / 547 (80.07%)
    435 / 529 (82.23%)
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    28 / 547 (5.12%)
    31 / 529 (5.86%)
         occurrences all number
    48
    86
    Headache
         subjects affected / exposed
    161 / 547 (29.43%)
    152 / 529 (28.73%)
         occurrences all number
    2409
    1658
    Paraesthesia
         subjects affected / exposed
    20 / 547 (3.66%)
    31 / 529 (5.86%)
         occurrences all number
    52
    48
    Multiple sclerosis relapse
         subjects affected / exposed
    130 / 547 (23.77%)
    155 / 529 (29.30%)
         occurrences all number
    208
    246
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    45 / 547 (8.23%)
    64 / 529 (12.10%)
         occurrences all number
    318
    441
    Chills
         subjects affected / exposed
    58 / 547 (10.60%)
    70 / 529 (13.23%)
         occurrences all number
    565
    527
    Fatigue
         subjects affected / exposed
    52 / 547 (9.51%)
    40 / 529 (7.56%)
         occurrences all number
    297
    155
    Injection site erythema
         subjects affected / exposed
    224 / 547 (40.95%)
    222 / 529 (41.97%)
         occurrences all number
    7819
    3621
    Influenza like illness
         subjects affected / exposed
    234 / 547 (42.78%)
    234 / 529 (44.23%)
         occurrences all number
    6506
    4105
    Injection site pain
         subjects affected / exposed
    34 / 547 (6.22%)
    38 / 529 (7.18%)
         occurrences all number
    162
    215
    Injection site pruritus
         subjects affected / exposed
    34 / 547 (6.22%)
    24 / 529 (4.54%)
         occurrences all number
    521
    134
    Pyrexia
         subjects affected / exposed
    132 / 547 (24.13%)
    147 / 529 (27.79%)
         occurrences all number
    2228
    1765
    Psychiatric disorders
    Depression
         subjects affected / exposed
    26 / 547 (4.75%)
    27 / 529 (5.10%)
         occurrences all number
    32
    30
    Insomnia
         subjects affected / exposed
    19 / 547 (3.47%)
    27 / 529 (5.10%)
         occurrences all number
    41
    39
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    34 / 547 (6.22%)
    25 / 529 (4.73%)
         occurrences all number
    146
    47
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    57 / 547 (10.42%)
    53 / 529 (10.02%)
         occurrences all number
    233
    192
    Arthralgia
         subjects affected / exposed
    52 / 547 (9.51%)
    49 / 529 (9.26%)
         occurrences all number
    535
    322
    Myalgia
         subjects affected / exposed
    67 / 547 (12.25%)
    65 / 529 (12.29%)
         occurrences all number
    1020
    781
    Pain in extremity
         subjects affected / exposed
    55 / 547 (10.05%)
    52 / 529 (9.83%)
         occurrences all number
    204
    166
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    49 / 547 (8.96%)
    68 / 529 (12.85%)
         occurrences all number
    79
    122
    Upper respiratory tract infection
         subjects affected / exposed
    34 / 547 (6.22%)
    18 / 529 (3.40%)
         occurrences all number
    47
    24
    Urinary tract infection
         subjects affected / exposed
    53 / 547 (9.69%)
    51 / 529 (9.64%)
         occurrences all number
    70
    75

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2011
    The BDI-II questionnaire was added as an additional safety assessment to monitor depression, which is a known side effect of interferon. The BDI-II is the same questionnaire that was used in Study 301 to monitor depression. The MES was added to the study activity chart to provide information on rebound effects in subjects who prematurely discontinued BIIB017 treatment. The MES added to Study 302 was the same as that offered in Study 301.
    24 Jul 2014
    The protocol was amended to remove the Q4W dosing group from the study. All subjects will now receive BIIB017 Q2W.

    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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