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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects with First Episode of Acute Optic Neuritis

    Summary
    EudraCT number
    2011-006291-39
    Trial protocol
    SE   BE   DE   CZ   GB   HU   ES   IT   DK  
    Global end of trial date
    21 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Mar 2016
    First version publication date
    24 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    215ON201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01721161
    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
    21 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of BIIB033 in subjects with their first episode of unilateral acute optic neuritis (AON). The secondary objective of this study in this population was to assess the safety, tolerability, and pharmacokinetics (PK) of BIIB033.
    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. Following study treatment administration, subjects were required to remain at the study site for 1 hour for monitoring of any unexpected infusion reactions. Medications for the treatment of severe hypersensitivity reactions (e.g., epinephrine for subcutaneous injections, diphenhydramine for IV injection) were available for immediate use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Dec 2012
    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
    Spain: 14
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    82
    EEA total number of subjects
    71
    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)
    82
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject eligibility for the study was determined within 28 days prior to Day -1. The daily course of IV methylprednisolone was completed before administration of the first dose of study treatment on Day 1/baseline.

    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
    Investigator, Subject
    Blinding implementation details
    This was a randomized, double-blinded, parallel-group, placebo-controlled study. All study staff were blinded to the subject treatment assignments (BIIB033 or placebo) with the exception of the unblinded Pharmacist or designee who was responsible for preparing the study treatments, the unblinded Pharmacy Monitor, and the study staff responsible for the analysis of the PK data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)
    Arm type
    Placebo

    Investigational medicinal product name
    sterile normal saline (0.9% sodium chloride for IV administration)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects who were randomized to placebo were dosed at 6 study visits (every 4 weeks for 20 weeks: Day 1/baseline, Week 4, Week 8, Week 12, Week 16, and Week 20) by IV infusion.

    Arm title
    BIIB033
    Arm description
    BIIB033 100 mg/kg via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)
    Arm type
    Experimental

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects were dosed at the Day 1/baseline Visit. Subsequent doses were administered once every 4 weeks for a total of 6 doses. Dosing schedule for each subject was as follows: Day 1/baseline, Week 4, Week 8, Week 12, Week 16, and Week 20.

    Number of subjects in period 1
    Placebo BIIB033
    Started
    41
    41
    Completed
    37
    34
    Not completed
    4
    7
         Adverse event, non-fatal
    2
    3
         Consent withdrawn by subject
    1
    1
         Not Specified
    -
    1
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)

    Reporting group title
    BIIB033
    Reporting group description
    BIIB033 100 mg/kg via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)

    Reporting group values
    Placebo BIIB033 Total
    Number of subjects
    41 41 82
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    32.4 ± 8.85 31.8 ± 7.17 -
    Gender, Male/Female
    Units: participants
        Female
    31 27 58
        Male
    10 14 24
    Affected eye
    Units: Subjects
        Right eye
    19 25 44
        Left eye
    22 16 38
    FF-VEP conduction block in the affected eye at baseline
    FF-VEP=full-field visual evoked potentials
    Units: Subjects
        FF-VEP conduction block
    5 10 15
        No FF-VEP conduction block
    36 31 67
    Days from first AON symptom to first dose
    First dose given, on average, 2 weeks after completion of high-dose (1 g daily for 3 to 5 days) IV methylprednisolone treatment.
    Units: days
        arithmetic mean (standard deviation)
    24.6 ± 3.4 23.6 ± 4 -
    Days from confirmed AON diagnosis to first dose
    Units: days
        arithmetic mean (standard deviation)
    19.2 ± 4.9 18.7 ± 4.7 -
    FF-VEP latency in the fellow eye at baseline
    Units: ms
        arithmetic mean (standard deviation)
    101.7 ± 5.25 102.7 ± 6.4 -
    RGCL/IPL thickness in the affected eye at baseline
    RGCL/IPL=retinal ganglion cell layer/inner plexiform retinal layer. n=38 in the placebo group and n=40 in the anti-LINGO-1 group, total n=78.
    Units: microns
        arithmetic mean (standard deviation)
    66 ± 6.9 63.8 ± 7.4 -
    Brain Gd+ lesions before first dose
    Gd+=gadolinium-enhancing. n=38 in each group, total n=76.
    Units: lesions
        arithmetic mean (standard deviation)
    0.5 ± 1.6 0.2 ± 1 -
    Volume of brain T2 lesions before first dose
    n=38 in each group, total n=76.
    Units: mL
        arithmetic mean (standard deviation)
    1.09 ± 1.32 1.09 ± 1.9 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)

    Reporting group title
    BIIB033
    Reporting group description
    BIIB033 100 mg/kg via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)

    Primary: Change in Full-field Visual Evoked Potential (FF-VEP) Latency at Week 24: Intent-to-treat (ITT) Population

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    End point title
    Change in Full-field Visual Evoked Potential (FF-VEP) Latency at Week 24: Intent-to-treat (ITT) Population
    End point description
    Adjusted mean change in optic nerve conduction velocity (NCV) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by FF-VEP. Adjusted for the baseline latency of fellow eye.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    41
    41
    Units: msec
        arithmetic mean (standard error)
    20.83 ± 2.53
    17.34 ± 2.53
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3337
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -3.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.61
         upper limit
    3.65

    Primary: Change in FF-VEP Latency at Week 24: Per-protocol Population

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    End point title
    Change in FF-VEP Latency at Week 24: Per-protocol Population
    End point description
    Adjusted mean change in optic nerve conduction velocity (NCV) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by FF-VEP. Adjusted for the baseline latency of fellow eye.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    36
    33
    Units: msec
        arithmetic mean (standard error)
    22.24 ± 2.61
    14.69 ± 2.72
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0504
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -7.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.12
         upper limit
    0.01

    Secondary: Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 24: ITT Population

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    End point title
    Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 24: ITT Population
    End point description
    Adjusted mean percentage change in thickness of the RNFL at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by SD-OCT. Percentage change is calculated as (affected eye - baseline of fellow eye)/baseline of fellow eye*100. Adjusted for the baseline RNFL thickness.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    39
    41
    Units: percentage change
        arithmetic mean (standard error)
    -11.77 ± 2.08
    -15.66 ± 2.03
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1868
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -3.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.7
         upper limit
    1.92

    Secondary: Percentage Change in SD-OCT Average RNFL Thickness at Week 24: Per-protocol Population

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    End point title
    Percentage Change in SD-OCT Average RNFL Thickness at Week 24: Per-protocol Population
    End point description
    Adjusted mean percentage change in thickness of the RNFL at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by SD-OCT. Percentage change is calculated as (affected eye - baseline of fellow eye)/baseline of fellow eye*100. Adjusted for the baseline RNFL thickness.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    35
    33
    Units: percentage change
        arithmetic mean (standard error)
    -12.22 ± 2.26
    -16.98 ± 2.33
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1488
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -4.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.26
         upper limit
    1.74

    Secondary: Change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 24: ITT Population

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    End point title
    Change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 24: ITT Population
    End point description
    Adjusted mean change in thicknesses of the RGCL/IPL at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by segmentation of SD-OCT. Adjusted for the baseline RGCL/IPL thickness.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    40
    41
    Units: µm
        arithmetic mean (standard deviation)
    -9.9 ± 1.2
    -11.05 ± 1.18
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4975
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.51
         upper limit
    2.21

    Secondary: Change in SD-OCT Average RGCL/IPL at Week 24: Per-protocol Population

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    End point title
    Change in SD-OCT Average RGCL/IPL at Week 24: Per-protocol Population
    End point description
    Adjusted mean change in thicknesses of the RGCL/IPL at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by segmentation of SD-OCT. Adjusted for the baseline RGCL/IPL thickness.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    36
    33
    Units: µm
        arithmetic mean (standard deviation)
    -10.17 ± 1.29
    -11.93 ± 1.35
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3505
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -1.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.5
         upper limit
    1.98

    Secondary: Change in Low-contrast Letter Acuity (LCLA) at Week 24: ITT Population

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    End point title
    Change in Low-contrast Letter Acuity (LCLA) at Week 24: ITT Population
    End point description
    Adjusted mean change in LCLA at Week 24 from baseline as determined by 1.25% and 2.5% low contrast Sloan letter charts, adjusted for the baseline LCLA value. The fellow eye is the reference eye for the inter-eye asymmetry. The range for LCLA assessment is 0-60.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    41
    39
    Units: letters on a chart
    arithmetic mean (standard deviation)
        LCLA 1.25% chart
    8.1 ± 1.8
    6.5 ± 1.9
        LCLA 2.5% chart
    11.9 ± 2
    11 ± 2
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    LCLA 1.25% chart
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5371
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.9
         upper limit
    3.6
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    LCLA 2.5% chart
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7741
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.5
         upper limit
    4.9

    Secondary: Change in LCLA at Week 24: Per-protocol Population

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    End point title
    Change in LCLA at Week 24: Per-protocol Population
    End point description
    Adjusted mean change in LCLA at Week 24 from baseline as determined by 1.25% and 2.5% low contrast Sloan letter charts, adjusted for the baseline LCLA value. The fellow eye is the reference eye for the inter-eye asymmetry. The range for LCLA assessment is 0-60.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo BIIB033
    Number of subjects analysed
    36
    33
    Units: letters on a chart
    arithmetic mean (standard error)
        LCLA 1.25% chart
    7.2 ± 1.8
    6 ± 2
        LCLA 2.5% chart
    11.6 ± 2
    10.8 ± 2.2
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    LCLA 1.25% chart
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6645
    Method
    ANCOVA
    Parameter type
    Difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.6
         upper limit
    4.3
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    LCLA 2.5%
    Comparison groups
    Placebo v BIIB033
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8015
    Method
    ANCOVA
    Parameter type
    DIfference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.7
         upper limit
    5.2

    Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    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 subject 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 subject or may have required intervention to prevent one of the other outcomes listed in the definition above.
    End point type
    Secondary
    End point timeframe
    32 weeks
    End point values
    Placebo BIIB033
    Number of subjects analysed
    41
    41
    Units: participants
        Participants with an event
    34
    34
        Participants with a moderate or severe event
    22
    21
        Participants with a severe event
    2
    3
        Participants with a related event
    8
    14
        Participants with a serious event
    2
    5
        Participants with a related serious event
    0
    3
        Participants discontinuing treatment due to event
    1
    3
        Participants withdrawing from study due to event
    2
    3
    No statistical analyses for this end point

    Secondary: Summary of BIIB033 Concentration

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    End point title
    Summary of BIIB033 Concentration [1]
    End point description
    One pre-dose pharmacokinetic (PK) sample and 1 post-dose PK sample (approximately between 1 and 3 hours after the end of IV infusion) were collected for all participants on Day 1 and at Weeks 4 through 20 (every 4 weeks). Additionally, only 1 PK sample was collected at Week 24 and Week 32. (There was no dosing on Week 24 and Week 32, so only one blood sample for BIIB033 concentration was taken.) Samples collected at early termination visits were treated as predose samples for the next scheduled visit.
    End point type
    Secondary
    End point timeframe
    Up to 32 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: PK values are not reported for the placebo group as no study drug was taken.
    End point values
    BIIB033
    Number of subjects analysed
    41
    Units: µg/mL
    median (full range (min-max))
        Baseline predose; n=41
    0 (0 to 3.22)
        Baseline postdose; n=40
    2030 (1370 to 3200)
        Week 4 predose; n=41
    375 (14.6 to 2960)
        Week 4 postdose; n=37
    2350 (368 to 3590)
        Week 8 predose; n=38
    537 (32.7 to 1130)
        Week 8 postdose; n=36
    2585 (550 to 4220)
        Week 12 predose; n=36
    622 (39.9 to 3230)
        Week 12 postdose; n=34
    2695 (542 to 4240)
        Week 16 predose; n=35
    593 (173 to 1320)
        Week 16 postdose; n=34
    2500 (1560 to 4590)
        Week 20 predose; n=37
    673 (107 to 4760)
        Week 20 postdose; n=35
    2530 (366 to 3990)
        Week 24; n=37
    624 (4.3 to 1060)
        Week 32; n=33
    82.7 (2.56 to 339)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were monitored from administration of first dose of study treatment through to Week 32 visit. SAEs were monitored from signing of the Informed Consent Form (ICF) through to Week 32 visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    BIIB033 100 mg/kg
    Reporting group description
    BIIB033 100 mg/kg via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)

    Reporting group title
    Placebo
    Reporting group description
    Placebo via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses)

    Serious adverse events
    BIIB033 100 mg/kg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 41 (4.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         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
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral pericarditis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BIIB033 100 mg/kg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 41 (65.85%)
    25 / 41 (60.98%)
    Nervous system disorders
    Dysaesthesia
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 41 (4.88%)
         occurrences all number
    3
    3
    Headache
         subjects affected / exposed
    11 / 41 (26.83%)
    11 / 41 (26.83%)
         occurrences all number
    25
    18
    Multiple sclerosis
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    Paraesthesia
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 41 (0.00%)
         occurrences all number
    5
    0
    Uhthoff's phenomenon
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 41 (14.63%)
         occurrences all number
    3
    6
    Visual field defect
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Colour blindness acquired
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 41 (14.63%)
    5 / 41 (12.20%)
         occurrences all number
    7
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 41 (12.20%)
    3 / 41 (7.32%)
         occurrences all number
    7
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 41 (2.44%)
         occurrences all number
    6
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 41 (7.32%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    12 / 41 (29.27%)
    13 / 41 (31.71%)
         occurrences all number
    15
    20
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 41 (4.88%)
         occurrences all number
    5
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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