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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Ranging Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex®

    Summary
    EudraCT number
    2011-006262-40
    Trial protocol
    CZ   IT   NL   HU   ES   GB  
    Global end of trial date
    29 Mar 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Apr 2017
    First version publication date
    08 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    215MS201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of BIIB033 in participants with active relapsing multiple sclerosis (MS) when used concurrently with Avonex. Secondary objectives of this study in this study population are to assess the safety, tolerability, and population pharmacokinetics of BIIB033 when used concurrently with Avonex.
    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
    Avonex at 30 μg administered IM once weekly is marketed around the world as a therapeutic agent for patients with relapsing forms of MS to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Efficacy has also been demonstrated in MS patients who have experienced a first clinical episode and have MRI features consistent with MS.
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 118
    Country: Number of subjects enrolled
    Serbia: 75
    Country: Number of subjects enrolled
    United States: 52
    Country: Number of subjects enrolled
    Czech Republic: 48
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Hungary: 7
    Worldwide total number of subjects
    419
    EEA total number of subjects
    246
    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)
    419
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were screened within 28 days prior to the first dose of study treatment.

    Pre-assignment period milestones
    Number of subjects started
    419
    Number of subjects completed
    418

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    randomized and not dosed: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer
    Blinding implementation details
    All study staff were blinded to the subject treatment assignments (BIIB033 plus Avonex or placebo plus Avonex) with the exception of the unblinded Pharmacist or designee, who was responsible for preparing the study treatments, and the unblinded Pharmacy Monitor. Avonex was supplied open label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo once every 4 weeks intravenous (IV) infusion up to Week 72. Avonex once-weekly intramuscular (IM) injection up to Week 84.
    Arm type
    Placebo

    Investigational medicinal product name
    sterile normal saline (0.9% sodium chloride)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The manufacturer’s directions for material storage and handling were followed, as were standard clinical practices for ensuring sterility of the material.

    Investigational medicinal product name
    Avonex
    Investigational medicinal product code
    Other name
    interferon beta-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Avonex was supplied as liquid prefilled (Luer lock) syringes (i.e., Avonex Prefilled Syringe) and autoinjector pens (i.e., Avonex Pen®) for self-administration by IM (or via a proxy) once weekly in countries in which the Avonex Pen is approved. In countries in which the Avonex Pen is not approved, the Avonex Prefilled Syringe was provided.

    Arm title
    BIIB033, 3 mg/kg
    Arm description
    BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
    Arm type
    Experimental

    Investigational medicinal product name
    Avonex
    Investigational medicinal product code
    Other name
    interferon beta-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Avonex was supplied as liquid prefilled (Luer lock) syringes (i.e., Avonex Prefilled Syringe) and autoinjector pens (i.e., Avonex Pen®) for self-administration by IM (or via a proxy) once weekly in countries in which the Avonex Pen is approved. In countries in which the Avonex Pen is not approved, the Avonex Prefilled Syringe was provided.

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Human anti-LINGO-1 monoclonal antibody
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 was administered by IV infusion following dilution into saline as specified in the Directions for Handling and Administration (DHA).

    Arm title
    BIIB033, 10 mg/kg
    Arm description
    BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
    Arm type
    Experimental

    Investigational medicinal product name
    Avonex
    Investigational medicinal product code
    Other name
    interferon beta-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Avonex was supplied as liquid prefilled (Luer lock) syringes (i.e., Avonex Prefilled Syringe) and autoinjector pens (i.e., Avonex Pen®) for self-administration by IM (or via a proxy) once weekly in countries in which the Avonex Pen is approved. In countries in which the Avonex Pen is not approved, the Avonex Prefilled Syringe was provided.

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Human anti-LINGO-1 monoclonal antibody
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 was administered by IV infusion following dilution into saline as specified in the Directions for Handling and Administration (DHA).

    Arm title
    BIIB033, 30 mg/kg
    Arm description
    BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
    Arm type
    Experimental

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Human anti-LINGO-1 monoclonal antibody
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 was administered by IV infusion following dilution into saline as specified in the Directions for Handling and Administration (DHA).

    Investigational medicinal product name
    Avonex
    Investigational medicinal product code
    Other name
    interferon beta-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Avonex was supplied as liquid prefilled (Luer lock) syringes (i.e., Avonex Prefilled Syringe) and autoinjector pens (i.e., Avonex Pen®) for self-administration by IM (or via a proxy) once weekly in countries in which the Avonex Pen is approved. In countries in which the Avonex Pen is not approved, the Avonex Prefilled Syringe was provided.

    Arm title
    BIIB033, 100 mg/kg
    Arm description
    BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
    Arm type
    Experimental

    Investigational medicinal product name
    Avonex
    Investigational medicinal product code
    Other name
    interferon beta-1a
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Avonex was supplied as liquid prefilled (Luer lock) syringes (i.e., Avonex Prefilled Syringe) and autoinjector pens (i.e., Avonex Pen®) for self-administration by IM (or via a proxy) once weekly in countries in which the Avonex Pen is approved. In countries in which the Avonex Pen is not approved, the Avonex Prefilled Syringe was provided.

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Human anti-LINGO-1 monoclonal antibody
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 was administered by IV infusion following dilution into saline as specified in the Directions for Handling and Administration (DHA).

    Number of subjects in period 1 [1]
    Placebo BIIB033, 3 mg/kg BIIB033, 10 mg/kg BIIB033, 30 mg/kg BIIB033, 100 mg/kg
    Started
    93
    45
    95
    93
    92
    Randomized and Dosed
    93
    45
    95
    93
    92
    Completed
    73
    40
    84
    68
    69
    Not completed
    20
    5
    11
    25
    23
         NotSpecified
    2
    1
    1
    3
    1
         Adverse event, serious fatal
    -
    -
    -
    1
    -
         Investigator Decision
    5
    -
    -
    4
    6
         Adverse event, non-fatal
    4
    2
    4
    7
    7
         Consent withdrawn by subject
    9
    2
    6
    8
    8
         Lost to follow-up
    -
    -
    -
    2
    1
    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: One subject in the BIIB033 30 mg/kg arm was randomized and not dosed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo once every 4 weeks intravenous (IV) infusion up to Week 72. Avonex once-weekly intramuscular (IM) injection up to Week 84.

    Reporting group title
    BIIB033, 3 mg/kg
    Reporting group description
    BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group title
    BIIB033, 10 mg/kg
    Reporting group description
    BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group title
    BIIB033, 30 mg/kg
    Reporting group description
    BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group title
    BIIB033, 100 mg/kg
    Reporting group description
    BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group values
    Placebo BIIB033, 3 mg/kg BIIB033, 10 mg/kg BIIB033, 30 mg/kg BIIB033, 100 mg/kg Total
    Number of subjects
    93 45 95 93 92 418
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    93 45 95 93 92 418
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.5 ± 9.29 36.5 ± 9.47 40.5 ± 9.78 40.9 ± 9.7 39.8 ± 9.1 -
    Gender, Male/Female
    Units: Subjects
        Female
    67 24 59 61 66 277
        Male
    26 21 36 32 26 141

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo once every 4 weeks intravenous (IV) infusion up to Week 72. Avonex once-weekly intramuscular (IM) injection up to Week 84.

    Reporting group title
    BIIB033, 3 mg/kg
    Reporting group description
    BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group title
    BIIB033, 10 mg/kg
    Reporting group description
    BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group title
    BIIB033, 30 mg/kg
    Reporting group description
    BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Reporting group title
    BIIB033, 100 mg/kg
    Reporting group description
    BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.

    Subject analysis set title
    BIIB033 Total
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    BIIB033 3, 10, 30, or 100 mg/kg once every 4 weeks IV infusion

    Primary: Proportion of Participants Confirmed as Improvement Responders for Primary Multicomponent Endpoint

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    End point title
    Proportion of Participants Confirmed as Improvement Responders for Primary Multicomponent Endpoint
    End point description
    Estimated proportion of participants experiencing confirmed improvement in any 1 or more of the following components: a ≥1 point decrease in the Expanded Disability Status Scale (EDSS) score from a baseline score of <=6.0 (decrease sustained for ≥3 months); a ≥15% improvement from baseline in time to complete 9-Hole Peg Test (9HPT) by either hand (improvement sustained for ≥3 months for the same hand), where the time is the average time of 2 trials per hand at the same visit; a ≥15% improvement from baseline in time to complete Timed 25-Foot Walk (T25FW) test (improvement sustained for ≥3 months), where the time is the average time of 2 trials at the same visit; or a ≥15% improvement from baseline 3-Second Paced Auditory Serial Addition Test (PASAT-3) score (improvement sustained for 3 months or greater). Estimated proportion of responders is based on logistic regression adjusted for multiple sclerosis (MS) type, region and baseline component assessments.
    End point type
    Primary
    End point timeframe
    72 weeks
    End point values
    Placebo BIIB033, 3 mg/kg BIIB033, 10 mg/kg BIIB033, 30 mg/kg BIIB033, 100 mg/kg
    Number of subjects analysed
    91
    45
    94
    91
    91
    Units: proportion of participants
        number (not applicable)
    0.516
    0.511
    0.656
    0.688
    0.412
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BIIB033, 3 mg/kg v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9584
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    2.07
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v BIIB033, 10 mg/kg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0636
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    3.31
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v BIIB033, 30 mg/kg
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.022
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.11
         upper limit
    3.84
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v BIIB033, 100 mg/kg
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1771
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    1.21
    Statistical analysis title
    Statistical Analysis 5
    Comparison groups
    Placebo v BIIB033, 3 mg/kg v BIIB033, 10 mg/kg v BIIB033, 30 mg/kg v BIIB033, 100 mg/kg
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8931
    Method
    Trend test
    Confidence interval

    Secondary: Proportion of Participants Confirmed as Worsening Responders for Primary Multicomponent Endpoint

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    End point title
    Proportion of Participants Confirmed as Worsening Responders for Primary Multicomponent Endpoint
    End point description
    Estimated proportion of participants experiencing confirmed clinical worsening in 1 or more components of the multicomponent endpoint (EDSS, T25FW, 9HPT, or PASAT-3) over 72 weeks, defined as: a ≥1.0 point increase in EDSS from a baseline score of ≤5.5 or a ≥0.5 point increase from a baseline score equal to 6.0 (increase sustained for 3 months or greater); a ≥15%worsening from baseline in time to complete T25FW test (worsening sustained for 3 months or greater), where the time is the average of 2 trials at the same visit; a ≥15% worsening from baseline in time to complete 9HPT by either hand (worsening sustained for 3 months or greater for the same hand), where the time is the average of 2 trials for each hand at the same visit; a ≥15% worsening from baseline in PASAT-3 score (worsening sustained for 3 months or greater). Estimated proportion of responders is based on logistic regression adjusted for MS type, region and baseline component assessments.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Placebo BIIB033, 3 mg/kg BIIB033, 10 mg/kg BIIB033, 30 mg/kg BIIB033, 100 mg/kg
    Number of subjects analysed
    91
    45
    94
    91
    91
    Units: proportion of participants
        number (not applicable)
    0.403
    0.304
    0.509
    0.489
    0.369
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033, 3 mg/kg
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3058
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    1.49
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v BIIB033, 10 mg/kg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1873
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    2.89
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v BIIB033, 30 mg/kg
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2766
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    2.65
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v BIIB033, 100 mg/kg
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6578
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    1.65
    Statistical analysis title
    Statistical Analysis 5
    Comparison groups
    Placebo v BIIB033, 3 mg/kg v BIIB033, 10 mg/kg v BIIB033, 30 mg/kg v BIIB033, 100 mg/kg
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5255
    Method
    Trend test
    Confidence interval

    Secondary: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) and Discontinuations Due to AEs

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    End point title
    Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) and Discontinuations Due to AEs
    End point description
    An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the participant at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused 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 Investigators, could have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above.
    End point type
    Secondary
    End point timeframe
    Up to 84 weeks
    End point values
    Placebo BIIB033, 3 mg/kg BIIB033, 10 mg/kg BIIB033, 30 mg/kg BIIB033, 100 mg/kg BIIB033 Total
    Number of subjects analysed
    93
    45
    95
    93
    92
    325
    Units: participants
        Any event
    79
    39
    84
    79
    73
    275
        Moderate or severe event
    59
    26
    59
    59
    58
    202
        Severe event
    7
    2
    6
    6
    7
    21
        BIIB033/placebo-related event
    8
    8
    15
    12
    16
    51
        Avonex-related event
    51
    28
    58
    54
    50
    190
        Serious event
    13
    4
    11
    20
    16
    51
        BIIB033/placebo-related serious event
    1
    0
    0
    1
    5
    6
        Avonex-related serious event
    1
    0
    0
    2
    1
    3
        Event leading to discontinuation of treatment
    4
    2
    3
    7
    8
    20
        Event leading to withdrawal from study
    4
    2
    4
    8
    7
    21
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: BIIB033 Plasma Concentrations up to Week 84

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    End point title
    Pharmacokinetics: BIIB033 Plasma Concentrations up to Week 84 [1]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 84 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: BIIB033 plasma concentrations are not applicable to the placebo arm.
    End point values
    BIIB033, 3 mg/kg BIIB033, 10 mg/kg BIIB033, 30 mg/kg BIIB033, 100 mg/kg
    Number of subjects analysed
    45
    95
    92
    92
    Units: µg/mL
    arithmetic mean (standard deviation)
        Baseline, predose; n=44, 95, 92, 92
    0 ± 0
    0.01 ± 0.13
    7.79 ± 74.75
    0.42 ± 4.07
        Baseline, postdose; n=44, 95, 91, 92
    66.7 ± 16
    244.76 ± 77.9
    688.47 ± 245.73
    2298.2 ± 712.91
        Week 4, predose; n=45, 93, 91, 88
    10.82 ± 4.11
    46.28 ± 33.15
    138.54 ± 92.82
    457.96 ± 308.09
        Week 4, postdose; n=45, 94, 89, 85
    123.96 ± 315.66
    279.67 ± 100.01
    784.08 ± 204.31
    2763.26 ± 823.42
        Week 8, predose; n=45, 95, 89, 85
    23.55 ± 54.96
    65.48 ± 52.53
    195.29 ± 118.24
    603.11 ± 425.58
        Week 8, postdose; n=44, 94, 88, 79
    86.29 ± 52.74
    294.44 ± 78.61
    861.6 ± 274.56
    2751.25 ± 697.42
        Week 16, predose; n=43, 94, 86, 79
    19.96 ± 9.74
    71.8 ± 25.13
    231.94 ± 125.42
    695.11 ± 438.57
        Week 16, postdose; n=41, 93, 85, 78
    85.95 ± 29.04
    309.38 ± 83.38
    881.45 ± 211.32
    2921.09 ± 1118.88
        Week 24, predose; n=42, 93, 85, 74
    36.41 ± 85.48
    77.88 ± 33.68
    230.46 ± 77.4
    699.63 ± 400.49
        Week 24, postdose; n=42, 92, 82, 76
    144.12 ± 373.36
    318.01 ± 84.74
    940.29 ± 231.35
    2870.29 ± 874.28
        Week 36, predose; n=41, 88, 79, 74
    25.33 ± 18.28
    85.05 ± 44.67
    238.48 ± 73.75
    725.22 ± 344.01
        Week 36, postdose; n=42, 88, 77, 73
    94.62 ± 21.89
    339.17 ± 88.96
    917.86 ± 197.96
    3048.66 ± 989.34
        Week 48, predose; n=39, 85, 74, 70
    20.78 ± 6.26
    80.28 ± 31.62
    272.88 ± 167.79
    806.7 ± 541.78
        Week 48, postdose; n=42, 85, 75, 72
    90.07 ± 23.37
    334.12 ± 78.43
    955.25 ± 193.34
    3167.07 ± 1144.25
        Week 60, predose; n=41, 84, 70, 68
    21.29 ± 12.34
    81.77 ± 30.24
    243.18 ± 78.57
    694.12 ± 200.41
        Week 60, postdose; n=42, 84, 71, 71
    93.11 ± 35.98
    335.1 ± 93.29
    939.17 ± 255.64
    3330.7 ± 1076.88
        Week 72, predose; n=41, 85, 72, 68
    19.53 ± 9.34
    78.94 ± 29.95
    215.09 ± 62.98
    819.39 ± 577.6
        Week 72, postdose; n=38, 84, 69, 68
    82.96 ± 31.84
    313.13 ± 87.22
    868.39 ± 231.14
    3145.82 ± 1233.66
        Week 84; n=40, 81, 69, 69
    2.44 ± 1.25
    12.77 ± 6.8
    46.16 ± 31.52
    127.69 ± 65.46
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dosing of study treatment through end of study (Week 84)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BIIB033 3 mg/kg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    BIIB033 30 mg/kg
    Reporting group description
    -

    Reporting group title
    BIIB033 100 mg/kg
    Reporting group description
    -

    Reporting group title
    BIIB033 10 mg/kg
    Reporting group description
    -

    Serious adverse events
    BIIB033 3 mg/kg Placebo BIIB033 30 mg/kg BIIB033 100 mg/kg BIIB033 10 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 45 (8.89%)
    13 / 93 (13.98%)
    20 / 93 (21.51%)
    16 / 92 (17.39%)
    11 / 95 (11.58%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    4 / 92 (4.35%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar i disorder
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 93 (1.08%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypochromic anaemia
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 93 (1.08%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 45 (4.44%)
    7 / 93 (7.53%)
    10 / 93 (10.75%)
    6 / 92 (6.52%)
    6 / 95 (6.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
    0 / 14
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 93 (1.08%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Secondary progressive multiple sclerosis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 93 (1.08%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 93 (1.08%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 93 (1.08%)
    0 / 93 (0.00%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 93 (0.00%)
    1 / 93 (1.08%)
    0 / 92 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 93 (2.15%)
    0 / 93 (0.00%)
    1 / 92 (1.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BIIB033 3 mg/kg Placebo BIIB033 30 mg/kg BIIB033 100 mg/kg BIIB033 10 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 45 (84.44%)
    74 / 93 (79.57%)
    70 / 93 (75.27%)
    67 / 92 (72.83%)
    79 / 95 (83.16%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 45 (0.00%)
    10 / 93 (10.75%)
    8 / 93 (8.60%)
    5 / 92 (5.43%)
    4 / 95 (4.21%)
         occurrences all number
    0
    12
    11
    7
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 93 (3.23%)
    6 / 93 (6.45%)
    7 / 92 (7.61%)
    5 / 95 (5.26%)
         occurrences all number
    2
    6
    8
    7
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 45 (17.78%)
    23 / 93 (24.73%)
    13 / 93 (13.98%)
    11 / 92 (11.96%)
    19 / 95 (20.00%)
         occurrences all number
    22
    115
    124
    40
    61
    Multiple sclerosis relapse
         subjects affected / exposed
    17 / 45 (37.78%)
    30 / 93 (32.26%)
    36 / 93 (38.71%)
    28 / 92 (30.43%)
    35 / 95 (36.84%)
         occurrences all number
    28
    50
    69
    38
    52
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 45 (2.22%)
    8 / 93 (8.60%)
    6 / 93 (6.45%)
    3 / 92 (3.26%)
    5 / 95 (5.26%)
         occurrences all number
    3
    21
    10
    4
    11
    Chills
         subjects affected / exposed
    4 / 45 (8.89%)
    5 / 93 (5.38%)
    8 / 93 (8.60%)
    4 / 92 (4.35%)
    4 / 95 (4.21%)
         occurrences all number
    16
    20
    29
    18
    18
    Fatigue
         subjects affected / exposed
    6 / 45 (13.33%)
    8 / 93 (8.60%)
    7 / 93 (7.53%)
    7 / 92 (7.61%)
    5 / 95 (5.26%)
         occurrences all number
    59
    9
    100
    16
    5
    Influenza like illness
         subjects affected / exposed
    17 / 45 (37.78%)
    37 / 93 (39.78%)
    34 / 93 (36.56%)
    38 / 92 (41.30%)
    51 / 95 (53.68%)
         occurrences all number
    81
    494
    456
    383
    962
    Pyrexia
         subjects affected / exposed
    9 / 45 (20.00%)
    7 / 93 (7.53%)
    12 / 93 (12.90%)
    11 / 92 (11.96%)
    8 / 95 (8.42%)
         occurrences all number
    43
    54
    36
    45
    35
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 93 (4.30%)
    2 / 93 (2.15%)
    3 / 92 (3.26%)
    5 / 95 (5.26%)
         occurrences all number
    0
    7
    2
    3
    7
    Depressed mood
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 93 (2.15%)
    2 / 93 (2.15%)
    1 / 92 (1.09%)
    1 / 95 (1.05%)
         occurrences all number
    3
    2
    2
    1
    1
    Depression
         subjects affected / exposed
    2 / 45 (4.44%)
    6 / 93 (6.45%)
    7 / 93 (7.53%)
    2 / 92 (2.17%)
    6 / 95 (6.32%)
         occurrences all number
    2
    8
    7
    2
    6
    Insomnia
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 93 (1.08%)
    6 / 93 (6.45%)
    5 / 92 (5.43%)
    4 / 95 (4.21%)
         occurrences all number
    2
    1
    7
    6
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 45 (11.11%)
    3 / 93 (3.23%)
    3 / 93 (3.23%)
    3 / 92 (3.26%)
    3 / 95 (3.16%)
         occurrences all number
    7
    3
    3
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 93 (3.23%)
    7 / 93 (7.53%)
    3 / 92 (3.26%)
    4 / 95 (4.21%)
         occurrences all number
    2
    3
    8
    6
    5
    Back pain
         subjects affected / exposed
    3 / 45 (6.67%)
    9 / 93 (9.68%)
    6 / 93 (6.45%)
    6 / 92 (6.52%)
    9 / 95 (9.47%)
         occurrences all number
    3
    9
    7
    10
    11
    Muscle spasms
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 93 (3.23%)
    2 / 93 (2.15%)
    1 / 92 (1.09%)
    2 / 95 (2.11%)
         occurrences all number
    3
    3
    2
    1
    8
    Musculoskeletal pain
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 93 (1.08%)
    2 / 93 (2.15%)
    2 / 92 (2.17%)
    1 / 95 (1.05%)
         occurrences all number
    3
    1
    2
    2
    1
    Myalgia
         subjects affected / exposed
    1 / 45 (2.22%)
    5 / 93 (5.38%)
    4 / 93 (4.30%)
    3 / 92 (3.26%)
    5 / 95 (5.26%)
         occurrences all number
    1
    74
    8
    4
    8
    Pain in extremity
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 93 (4.30%)
    7 / 93 (7.53%)
    1 / 92 (1.09%)
    5 / 95 (5.26%)
         occurrences all number
    5
    6
    15
    2
    5
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 45 (6.67%)
    4 / 93 (4.30%)
    4 / 93 (4.30%)
    6 / 92 (6.52%)
    6 / 95 (6.32%)
         occurrences all number
    3
    5
    4
    6
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 45 (6.67%)
    16 / 93 (17.20%)
    8 / 93 (8.60%)
    10 / 92 (10.87%)
    12 / 95 (12.63%)
         occurrences all number
    5
    27
    11
    17
    22
    Pharyngitis
         subjects affected / exposed
    5 / 45 (11.11%)
    2 / 93 (2.15%)
    3 / 93 (3.23%)
    3 / 92 (3.26%)
    4 / 95 (4.21%)
         occurrences all number
    5
    3
    3
    3
    4
    Sinusitis
         subjects affected / exposed
    2 / 45 (4.44%)
    5 / 93 (5.38%)
    0 / 93 (0.00%)
    2 / 92 (2.17%)
    2 / 95 (2.11%)
         occurrences all number
    2
    6
    0
    2
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 45 (8.89%)
    13 / 93 (13.98%)
    11 / 93 (11.83%)
    9 / 92 (9.78%)
    21 / 95 (22.11%)
         occurrences all number
    5
    14
    16
    14
    29
    Urinary tract infection
         subjects affected / exposed
    7 / 45 (15.56%)
    12 / 93 (12.90%)
    9 / 93 (9.68%)
    13 / 92 (14.13%)
    14 / 95 (14.74%)
         occurrences all number
    15
    13
    13
    22
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2012
    The primary reasons for the first global amendment (Version 2), dated 19 December 2012, were to change the information for the conrtact research organization associated with this study, change the use of the Avonex Prefilled Syringe to only Weeks 0 to 3, add the use of the Avonex Pen for the weeks after Week 3, make it mandatory that subjects titrate Avonex in Month 1 using the Avostartgrip Titration Kit and Prefilled Syringes, and define the DSRC and its members.
    10 Mar 2015
    The primary reason for the second global amendment (Version 3), dated 10 March 2015, was to include Avonex assignment during the 3-month safety Follow-Up Period (Weeks 72 to 84).
    18 Aug 2015
    The primary reason for the third global amendment (Version 4) was to omit the interim analysis. Additionally, the following 4 MRI endpoints for pre-existing brain lesions were made optional and ultimately were not measured in this study: - Change in magnetization transfer ratio (MTR) from Baseline for abnormal T1 volume. - Change in MTR from Baseline for abnormal T2 volume not associated with T1 hypointensity. - Change in diffusion tensor imaging (DTI) from Baseline for abnormal T1 volume. - Change in DTI from Baseline for abnormal T2 volume not associated with T1 hypointensity.

    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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