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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With Optional Open-Label Extension in Subjects With Relapsing Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-On Therapy to Anti-Inflammatory Disease-Modifying Therapies

    Summary
    EudraCT number
    		 2017-001224-22
    Trial protocol
    		 GB   DE   CZ   HU   BE   NL   ES   PL   IT  
    Global end of trial date
    12 Feb 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 May 2022
    First version publication date
    01 Mar 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    215MS202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03222973
    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
    12 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of Part 1 of this study was to evaluate the effects of BIIB033 versus placebo on disability improvement over 72 weeks. The primary objective of Part 2 of this study was to evaluate the long-term safety profile of BIIB033 as an add-on therapy in subjects with multiple sclerosis (MS). The secondary objective of Part 1 was to evaluate the effects of BIIB033 versus placebo on additional measures of disability improvement. The secondary objective of Part 2 was to investigate long-term efficacy (disability improvement) and additional safety measures of BIIB033 as an add-on therapy in subjects with MS.
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative, as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 Disease modifying therapy (DMT) - The DMTs were a stable dose of Interferon-beta (IFN β) (Avonex, Plegridy, Betaferon/Betaseron, or Rebif), dimethyl fumarate (DMF) (Tecfidera), and natalizumab (Tysabri), representing different mechanisms of action, anti inflammatory activities, and routes of administration. Based on the clinical judgment of the treating neurologist, subject can switch to another marketed DMT during the study (not limited to protocol-defined DMTs) or may discontinue the DMT altogether.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Czechia: 34
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 90
    Worldwide total number of subjects
    263
    EEA total number of subjects
    129
    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)
    263
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at the investigative sites in the Australia, Belgium, Canada, Czech Republic, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom and United States from 15 November 2017 to 12 February 2021.

    Pre-assignment
    Screening details
    		 A total of 263 subjects with relapsing multiple sclerosis (RMS) were randomised in Part 1 (Placebo-controlled) of the study to receive BIIB033 or placebo. Subjects who completed Part 1 and were eligible were enrolled into Part 2 (Open-label) of the study to receive BIIB033.

    Period 1
    Period 1 title
    Part 1 (Week 0 to Week 72)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Placebo
    Arm description
    		 Subjects with RMS received placebo intravenously (IV) as an add-on therapy to a background disease-modifying therapy (DMT) once every 4 weeks over 72 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    BIIB033-matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033-matching placebo administered via IV infusion, once every 4 weeks over 72 weeks.

    Arm title
    		 Part 1: BIIB033 750 mg
    Arm description
    		 Subjects with RMS received BIIB033 750 milligrams (mg) IV as an add-on therapy to a background DMT once every 4 weeks over 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Opicinumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 750 mg administered via IV infusion, once every 4 weeks over 72 weeks.

    Number of subjects in period 1
    		Part 1: Placebo Part 1: BIIB033 750 mg
    Started
    131
    132
    Intent-to-treat (ITT) Population
    131
    132
    Safety Population
    131
    132
    Completed
    107
    118
    Not completed
    24
    14
         Adverse Event
    3
    -
         Death
    -
    1
         Not Specified
    8
    2
         Pregnancy
    -
    1
         Lost to follow-up
    1
    1
         Consent Withdrawn
    12
    9
    Period 2
    Period 2 title
    Part 2 (Week 73 to Week 168)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 2: Placebo to BIIB033 750 mg
    Arm description
    		 Subjects who received placebo and completed Part 1 were enrolled into Part 2 to receive BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks for up to a maximum of 80 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Opicinumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 750 mg administered via IV infusion, once every 4 weeks over 80 weeks.

    Arm title
    		 Part 2: BIIB033 750 mg
    Arm description
    		 Subjects who received BIIB033 and completed Part 1 were enrolled into Part 2 to receive BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks for up to a maximum of 77 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB033
    Investigational medicinal product code
    Other name
    Opicinumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB033 750 mg administered via IV infusion, once every 4 weeks over 77 weeks.

    Number of subjects in period 2 [1]
    		Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Started
    101
    113
    ITT Population
    101
    113
    Safety Population
    101
    113
    Completed
    0
    0
    Not completed
    101
    113
         Subjects Not Dosed
    1
    -
         Adverse Event
    2
    -
         Pregnancy
    2
    1
         Not Specified
    84
    100
         Investigator Decision
    2
    1
         Consent Withdrawn
    10
    11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 11 subjects who completed Part 1 did not enter Part 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Subjects with RMS received placebo intravenously (IV) as an add-on therapy to a background disease-modifying therapy (DMT) once every 4 weeks over 72 weeks.

    Reporting group title
    Part 1: BIIB033 750 mg
    Reporting group description
    		 Subjects with RMS received BIIB033 750 milligrams (mg) IV as an add-on therapy to a background DMT once every 4 weeks over 72 weeks.

    Reporting group values
    		 Part 1: Placebo Part 1: BIIB033 750 mg Total
    Number of subjects
    		 131 132 263
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.7 ( 9.25 ) 39.4 ( 9.12 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 79 90 169
        Male
    		 52 42 94
    Race
    Units: Subjects
        Asian
    		 1 0 1
        Black or African American
    		 4 10 14
        White
    		 122 118 240
        Not Reported or Unknown
    		 4 4 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 13 18
        Not Hispanic or Latino
    		 123 116 239
        Unknown or Not Reported
    		 3 3 6

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Subjects with RMS received placebo intravenously (IV) as an add-on therapy to a background disease-modifying therapy (DMT) once every 4 weeks over 72 weeks.

    Reporting group title
    Part 1: BIIB033 750 mg
    Reporting group description
    		 Subjects with RMS received BIIB033 750 milligrams (mg) IV as an add-on therapy to a background DMT once every 4 weeks over 72 weeks.
    Reporting group title
    Part 2: Placebo to BIIB033 750 mg
    Reporting group description
    		 Subjects who received placebo and completed Part 1 were enrolled into Part 2 to receive BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks for up to a maximum of 80 weeks.

    Reporting group title
    Part 2: BIIB033 750 mg
    Reporting group description
    		 Subjects who received BIIB033 and completed Part 1 were enrolled into Part 2 to receive BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks for up to a maximum of 77 weeks.

    Primary: Part 1: Overall Response Score (ORS)

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    End point title
    		 Part 1: Overall Response Score (ORS)
    End point description
    ORS is a multicomponent score based on 4 components: Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test in dominant hand (9HPT-D), and 9HPT in nondominant hand (9HPT-ND). Overall Score=sum of 4 components at each visit [Range: +4 (improvement) to -4 (worsening)]. At each visit, each component is given a score relative to baseline (BL): -1 if threshold is met for worsening, 0 if no changes meet threshold criteria, or +1 if threshold is met for improvement. For T25FW and 9HPT improvement: ≥15% decrease in time from BL and worsening: ≥15% increase in time from BL. For EDSS, improvement: ≥1.0-point decrease in EDSS from BL score ≤6.0, worsening: ≥1-point increase from a BL score ≤5.5 or ≥0.5-point increase from BL score=6.0. Positive ORS=improvement in more components than there was worsening. ITT population=all randomised subjects who received at least 1 dose of study treatment. Subjects were analysed according to their treatment assignment.
    End point type
    Primary
    End point timeframe
    Part 1: Baseline to Week 72
    End point values
    		 Part 1: Placebo Part 1: BIIB033 750 mg
    Number of subjects analysed
    131
    132
    Units: score on a scale
        arithmetic mean (confidence interval 95%)
    -0.04 (-0.18 to 0.11)
    0.11 (-0.03 to 0.25)
    Statistical analysis title
    		 Over 72 weeks: Overall Response Score
    Comparison groups
    Part 1: Placebo v Part 1: BIIB033 750 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1479 [1]
    Method
    		 MMRM
    Parameter type
    		 Treatment Difference
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.35
    Notes
    [1] - P-values were based on the Mixed Model for Repeated Measures (MMRM) adjusted for background DMT group, baseline magnetization transfer ratio (MTR)/diffusion tensor imaging (DTI) category and baseline component assessments.

    Primary: Part 2: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Part 2: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [2]
    End point description
    An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. Safety population included all subjects who received at least 1 dose of study treatment. Subjects were analysed based on the actual treatment allocation.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline to Week 169
    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: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    100
    113
    Units: subjects
        AEs
    71
    76
        SAEs
    9
    2
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND

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    End point title
    		 Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND
    End point description
    EDSS measures disability status over time in MS (scale range: 0-10), higher scores=more disability and improvement is ≥1.0-point decrease in EDSS from BL score ≤6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL indicates improvement. ITT population included all randomised subjects who received at least 1 dose of study treatment. Subjects were analysed according to their treatment assignment regardless of actual treatment received.
    End point type
    Secondary
    End point timeframe
    Part 1: Baseline to Week 72
    End point values
    		 Part 1: Placebo Part 1: BIIB033 750 mg
    Number of subjects analysed
    131
    132
    Units: percentage of subjects
        number (not applicable)
    37
    39
    Statistical analysis title
    		 Part 1: Placebo vs BIIB033 750 mg
    Comparison groups
    Part 1: Placebo v Part 1: BIIB033 750 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7682 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.79
    Notes
    [3] - Odds ratio (active vs. placebo), 95% CI and p-value were based on logistic regression adjusted for background DMT group, baseline MTR/DTI category and baseline component assessments.

    Secondary: Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3)

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    End point title
    		 Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3)
    End point description
    EDSS measures disability status over time in MS (scale range: 0-10), higher scores=more disability and improvement is ≥1.0-point decrease in EDSS from BL score ≤6.0. T25FW is quantitative mobility and leg function performance test, where timed walk over 25 feet that is averaged between two completed trials. Longer time=slower walking. 9HPT is quantitative test of upper extremity function, measures time to place 9 pegs into 9 holes and then remove pegs. Longer time=poorer upper limb function. PASAT assesses auditory information processing speed. In 3-second PASAT, numbers are presented at a rate of 1 every 3 seconds with scores (range 0-120), higher scores=better working memory. For T25FW and 9HPT ≥15% decrease in time from BL is improvement. For PASAT ≥15% increase from BL is improvement. ITT population.
    End point type
    Secondary
    End point timeframe
    Part 1: Baseline to Week 72
    End point values
    		 Part 1: Placebo Part 1: BIIB033 750 mg
    Number of subjects analysed
    131
    132
    Units: percentage of subjects
        number (not applicable)
    60
    52
    Statistical analysis title
    		 Part 1: Placebo vs BIIB033 750 mg
    Comparison groups
    Part 1: Placebo v Part 1: BIIB033 750 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2131 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.22
    Notes
    [4] - Odds ratio (active vs. placebo), 95% CI and p-value were based on logistic regression adjusted for background DMT group, baseline MTR/DTI category and baseline component assessments.

    Secondary: Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in any of the 4 Assessments During the 72 Weeks of the Study

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    End point title
    		 Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in any of the 4 Assessments During the 72 Weeks of the Study
    End point description
    EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS from a BL score of ≤6.0, and worsening is defined as a ≥1-point increase from a BL score of ≤5.5 or a ≥0.5-point increase from a BL score equal to 6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL indicates improvement and ≥15% increase in time from BL indicates worsening. ITT population.
    End point type
    Secondary
    End point timeframe
    Part 1: Baseline to Week 72
    End point values
    		 Part 1: Placebo Part 1: BIIB033 750 mg
    Number of subjects analysed
    131
    132
    Units: percentage of subjects
        number (not applicable)
    31
    28
    Statistical analysis title
    		 Part 1: Placebo vs BIIB033 750 mg
    Comparison groups
    Part 1: Placebo v Part 1: BIIB033 750 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4654 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.41
    Notes
    [5] - Odds ratio (active vs. placebo), 95% CI and p-value were based on logistic regression adjusted for background DMT group, baseline MTR/DTI category and baseline component assessments.

    Secondary: Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT)

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    End point title
    		 Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT)
    End point description
    EDSS measures disability status over time in MS on a scale (range 0-10), higher scores=more disability. For EDSS, improvement is a ≥1.0-point decrease in EDSS from a BL score of ≤6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time=slower walking. 9HPT is quantitative test of upper extremity function that measures time it takes to place 9 pegs into 9 holes and then remove pegs. Longer time=poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL is improvement. The SDMT measures time to pair abstract geometric symbols with specific numbers. The score is the number of correctly coded items (range 0-110) in 90 seconds, higher scores=better outcome. Improvement is: ≥4-point increase from BL. ITT population.
    End point type
    Secondary
    End point timeframe
    Part 1: Baseline to Week 72
    End point values
    		 Part 1: Placebo Part 1: BIIB033 750 mg
    Number of subjects analysed
    131
    132
    Units: percentage of subjects
        number (not applicable)
    63
    75
    Statistical analysis title
    		 Part 1: Placebo vs BIIB033 750 mg
    Comparison groups
    Part 1: Placebo v Part 1: BIIB033 750 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0417 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 3.11
    Notes
    [6] - Odds ratio (active vs. placebo), 95% CI and p-value were based on logistic regression adjusted for background DMT group, baseline MTR/DTI category and baseline component assessments.

    Secondary: Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)

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    End point title
    		 Part 1: Percentage of Subjects with 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)
    End point description
    EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS from a BL score of ≤6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL indicates improvement. ITT population.
    End point type
    Secondary
    End point timeframe
    Part 1: Baseline to Week 72
    End point values
    		 Part 1: Placebo Part 1: BIIB033 750 mg
    Number of subjects analysed
    131
    132
    Units: percentage of subjects
        number (not applicable)
    25
    32
    Statistical analysis title
    		 Part 1: Placebo vs BIIB033 750 mg
    Comparison groups
    Part 1: Placebo v Part 1: BIIB033 750 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2908 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.33
    Notes
    [7] - Odds ratio (active vs. placebo), 95% CI and p-value were based on logistic regression adjusted for background DMT group, baseline MTR/DTI category and baseline component assessments.

    Secondary: Part 2: Overall Response Score

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    End point title
    		 Part 2: Overall Response Score
    End point description
    Part 1 of Study 215MS202 failed to meet its primary endpoint of ORS over 72 weeks. Trial also failed to show efficacy in its secondary endpoints. Thus, Sponsor decided to terminate Part 2 of study early, and no participants had the opportunity to complete Part 2 of the study. No data was collected as per the protocol prespecified Part 2 efficacy analyses to assess the long-term efficacy of BIIB033 in Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: score on a scale
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [8] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    [9] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND

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    End point title
    		 Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND
    End point description
    Part 1 of Study 215MS202 failed to meet its primary endpoint of ORS over 72 weeks. Trial also failed to show efficacy in its secondary endpoints. Thus, Sponsor decided to terminate Part 2 of study early, and no participants had the opportunity to complete Part 2 of the study. No data was collected as per the protocol prespecified Part 2 efficacy analyses to assess the long-term efficacy of BIIB033 in Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 108
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [10] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    [11] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or PASAT-3

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    End point title
    		 Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or PASAT-3
    End point description
    Part 1 of Study 215MS202 failed to meet its primary endpoint of ORS over 72 weeks. Trial also failed to show efficacy in its secondary endpoints. Thus, Sponsor decided to terminate Part 2 of study early, and no participants had the opportunity to complete Part 2 of the study. No data was collected as per the protocol prespecified Part 2 efficacy analyses to assess the long-term efficacy of BIIB033 in Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 108
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [12] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    [13] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in any of the 4 Assessments During the 96 Weeks of the Study

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    End point title
    		 Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in any of the 4 Assessments During the 96 Weeks of the Study
    End point description
    Part 1 of Study 215MS202 failed to meet its primary endpoint of ORS over 72 weeks. Trial also failed to show efficacy in its secondary endpoints. Thus, Sponsor decided to terminate Part 2 of study early, and no participants had the opportunity to complete Part 2 of the study. No data was collected as per the protocol prespecified Part 2 efficacy analyses to assess the long-term efficacy of BIIB033 in Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [14] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    [15] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and SDMT

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    End point title
    		 Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and SDMT
    End point description
    Part 1 of Study 215MS202 failed to meet its primary endpoint of ORS over 72 weeks. Trial also failed to show efficacy in its secondary endpoints. Thus, Sponsor decided to terminate Part 2 of study early, and no participants had the opportunity to complete Part 2 of the study. No data was collected as per the protocol prespecified Part 2 efficacy analyses to assess the long-term efficacy of BIIB033 in Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 108
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [16] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    [17] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)

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    End point title
    		 Part 2: Percentage of Subjects with 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)
    End point description
    Part 1 of Study 215MS202 failed to meet its primary endpoint of ORS over 72 weeks. Trial also failed to show efficacy in its secondary endpoints. Thus, Sponsor decided to terminate Part 2 of study early, and no participants had the opportunity to complete Part 2 of the study. No data was collected as per the protocol prespecified Part 2 efficacy analyses to assess the long-term efficacy of BIIB033 in Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 108
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [18] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    [19] - Part 2 efficacy analyses was not performed since study was early terminated due to lack of efficacy.
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects with Potentially Clinically Significant Abnormal Laboratory Values

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    End point title
    		 Part 2: Number of Subjects with Potentially Clinically Significant Abnormal Laboratory Values
    End point description
    Laboratory assessments-hematology, blood chemistry were evaluated for safety. Safety population. Number analysed (n)=number of subjects analysed for this endpoint. Abnormality criteria: In 10^9/liter (L) [white blood cells <3.0/>16, neutrophils <1.5/ >13.5, lymphocytes <0.8/ >12, monocytes >2.5, eosinophils >1.6, basophils >1.6, platelets <=75/ >=700], hemoglobin <=95 [female (F)] or <=115 [male (M)] or >=175 (F) or >=190 (M) gram per L (g/L), hematocrit <=32 (F) or <=37 (M) or >=54 (F) or >=60 (M) percentage (%), red blood cells <=3.5/ >=6.4 10^12/L, in millimoles (mmol)/L [sodium <=126/ >=156, potassium <=3/ >=6, chloride <=90/ >=118, bicarbonate <=16/ >=35, calcium <=2/ >=3, phosphorous <=0.5491/ >=1.7119, glucose (non-fasting) <=2.2/>=13.75], AST/SGOT >=3x upper limit of normal (ULN), ALT/SGPT >=3xULN, alkaline phosphatase >=3xULN, creatinine >=1.5xULN, total bilirubin >=1.5xULN, total protein <=45/ >=100 g/L,albumin <=25 g/L,uric acid >=501.5 (F)/>=619.5 (M) micromole (umol)/L.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    100
    113
    Units: subjects
        White blood cells[10^9/L]:<3.0(n=98,113)
    3
    3
        White blood cells (10^9/L): >16 (n=98,113)
    2
    0
        Neutrophils (10^9/L): <1.5 (n=98,113)
    3
    3
        Neutrophils (10^9/L): >13.5 (n=98,113)
    0
    0
        Lymphocytes (10^9/L): <0.8 (n=98,113)
    13
    15
        Lymphocytes (10^9/L): >12 (n=98,113)
    1
    0
        Monocytes (10^9/L): >2.5 (n=98,113)
    0
    0
        Eosinophils (10^9/L): >1.6 (n=98,113)
    1
    0
        Basophils (10^9/L): >1.6 (n=98,113)
    0
    0
        Hemoglobin (g/L): <=95 (F) / <=115 (M)(n=98,113)
    0
    2
        Hemoglobin (g/L): >=175 (F) / >=190 (M)(n=98,113)
    0
    0
        Hematocrit (%): <=32 (F) or <=37 (M) (n=98,113)
    2
    5
        Hematocrit (%): >=54 (F) or >=60 (M) (n=98,113)
    0
    0
        Red blood cells (10^12/L): <=3.5 (n=98,113)
    0
    0
        Red blood cells (10^12/L): >=6.4 (n=98,113)
    0
    0
        Platelets (10^9/L): <=75 (n=98,113)
    0
    0
        Platelets (10^9/L): >=700 (n=98,113)
    0
    0
        Sodium (mmol/L): <=126
    0
    0
        Sodium (mmol/L): >=156
    0
    0
        Potassium (mmol/L): <=3
    0
    1
        Potassium (mmol/L): >=6
    0
    0
        Chloride (mmol/L): <=90
    0
    0
        Chloride (mmol/L): >=118
    0
    0
        Bicarbonate (mmol/L): <=16
    1
    1
        Bicarbonate (mmol/L): >=35
    0
    0
        Calcium (mmol/L): <=2
    0
    1
        Calcium (mmol/L): >=3
    0
    0
        Phosphorus (mmol/L): <=0.5491
    0
    1
        Phosphorus (mmol/L): >=1.7119
    0
    0
        Aspartate aminotransferase (AST)/SGOT: >=3xULN
    0
    0
        Alanine aminotransferase (ALT)/SGPT: >=3xULN
    0
    0
        Alkaline phosphatase: >=3xULN
    0
    0
        Creatinine: >=1.5xULN
    0
    0
        Total bilirubin: >=1.5xULN
    0
    1
        Total protein (g/L): <=45
    0
    0
        Total protein (g/L): >=100
    0
    0
        Albumin (g/L): <=25
    0
    0
        Uric acid (umol)/L: >=501.5 (F)/>=619.5 (M)
    1
    0
        Glucose (non-fasting) (mmol/L): <=2.2
    0
    0
        Glucose (non-fasting) (mmol/L): >=13.75
    1
    1
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects with Potentially Clinically Significant Electrocardiogram (ECG) Values

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    End point title
    		 Part 2: Number of Subjects with Potentially Clinically Significant Electrocardiogram (ECG) Values
    End point description
    The ECG result was classified was “normal”, “abnormal”, “abnormal, not adverse event”, or “abnormal, adverse event”. Shift to 'abnormal, not adverse event' included shift from normal or unknown to 'abnormal, not adverse event'. Shift to 'abnormal, adverse event' included shift from normal or unknown to 'abnormal, adverse event'. Safety population included all subjects who received at least 1 dose of study treatment. Subjects were analysed based on the actual treatment allocation. 'Number analysed (n)’ signifies number of subjects analysed at the specified timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    100
    113
    Units: subjects
        At Day (D) 1: Normal
    83
    89
        At D1: Abnormal, not Adverse Event (AE)
    10
    16
        D1 to Week(W)12:Shift to Abnormal,not AE(n=80,82)
    7
    6
        D1 to W12: Shift to Abnormal, AE (n=80,82)
    1
    0
        D1 to W24: Shift to Abnormal, not AE (n=79,88)
    4
    8
        D1 to W24: Shift to Abnormal, AE (n=79,88)
    0
    0
        D1 to W36: Shift to Abnormal, not AE (n=75,85)
    3
    10
        D1 to W36: Shift to Abnormal, AE (n=75,85)
    0
    1
        D1 to W48: Shift to Abnormal, not AE (n=71,79)
    2
    7
        D1 to W48: Shift to Abnormal, AE (n=71,79)
    0
    1
        D1 to W60: Shift to Abnormal, not AE (n=52,50)
    3
    5
        D1 to W60: Shift to Abnormal, AE (n=52,50)
    0
    0
        D1 to W72: Shift to Abnormal, not AE (n=23,23)
    1
    2
        D1 to W72: Shift to Abnormal, AE (n=23,23)
    0
    0
        D1 to W84: Shift to Abnormal, not AE (n=4,8)
    0
    2
        D1 to W84: Shift to Abnormal, AE (n=4,8)
    0
    0
        D1 to W96: Shift to Abnormal, not AE (n=2,0)
    0
    0
        D1 to W96: Shift to Abnormal, AE (n=2,0)
    0
    0
        At W12: Normal
    80
    81
        At W12: Abnormal, not AE
    9
    16
        At W12: Abnormal, AE
    1
    0
        W12 to W24: Shift to Abnormal, not AE (n=79,87)
    4
    7
        W12 to W24: Shift to Abnormal, AE (n=79,87)
    0
    0
        W12 to W36: Shift to Abnormal, not AE (n=76,86)
    4
    8
        W12 to W36: Shift to Abnormal, AE (n=76,86)
    0
    0
        W12 to W48: Shift to Abnormal, not AE (n=73,81)
    3
    6
        W12 to W48: Shift to Abnormal, AE (n=73,81)
    0
    2
        W12 to W60: Shift to Abnormal, not AE (n=54,52)
    5
    5
        W12 to W60: Shift to Abnormal, AE (n=54,52)
    0
    0
        W12 to W72: Shift to Abnormal, not AE (n=26,24)
    2
    1
        W12 to W72: Shift to Abnormal, AE (n=26,24)
    0
    0
        W12 to W84: Shift to Abnormal, not AE (n=6,7)
    0
    2
        W12 to W84: Shift to Abnormal, AE (n=6,7)
    0
    0
        W12 to W96: Shift to Abnormal, not AE (n=2,0)
    0
    0
        W12 to W96: Shift to Abnormal, AE (n=2,0)
    0
    0
        At W24: Normal
    83
    83
        At W24: Abnormal, not AE
    6
    20
        W24 to W36: Shift to Abnormal, not AE (n=78,81)
    5
    4
        W24 to W36: Shift to Abnormal, AE (n=78,81)
    0
    1
        W24 to W48: Shift to Abnormal, not AE (n=74,77)
    1
    5
        W24 to W48: Shift to Abnormal, AE (n=74,77)
    0
    1
        W24 to W60: Shift to Abnormal, not AE (n=56,50)
    4
    3
        W24 to W60: Shift to Abnormal, AE (n=56,50)
    0
    0
        W24 to W72: Shift to Abnormal, not AE (n=27,22)
    2
    1
        W24 to W72: Shift to Abnormal, AE (n=27,22)
    0
    0
        W24 to W84: Shift to Abnormal, not AE (n=6,5)
    0
    2
        W24 to W84: Shift to Abnormal, AE (n=6,5)
    0
    0
        W24 to W96: Shift to Abnormal, not AE (n=3,0)
    0
    0
        W24 to W96: Shift to Abnormal, AE (n=3,0)
    0
    0
        At W36: Normal
    77
    80
        At W36: Abnormal, not AE
    7
    20
        At W36: Abnormal, AE
    0
    1
        W36 to W48: Shift to Abnormal, not AE (n=75,75)
    3
    3
        W36 to W48: Shift to Abnormal, AE (n=75,75)
    0
    2
        W36 to W60: Shift to Abnormal, not AE (n=57,51)
    6
    5
        W36 to W60: Shift to Abnormal, AE (n=57,51)
    0
    0
        W36 to W72: Shift to Abnormal, not AE (n=26,24)
    2
    1
        W36 to W72: Shift to Abnormal, AE (n=26,24)
    0
    0
        W36 to W84: Shift to Abnormal, not AE (n=5,7)
    0
    2
        W36 to W84: Shift to Abnormal, AE (n=5,7)
    0
    0
        W36 to W96: Shift to Abnormal, not AE (n=3,0)
    0
    0
        W36 to W96: Shift to Abnormal, AE (n=3,0)
    0
    0
        At W48: Normal
    74
    76
        At W48: Abnormal, not AE
    4
    15
        At W48: Abnormal, AE
    0
    2
        W48 to W60: Shift to Abnormal, not AE (n=56,52)
    4
    4
        W48 to W60: Shift to Abnormal, AE (n=56,52)
    0
    0
        W48 to W72: Shift to Abnormal, not AE (n=27,24)
    2
    2
        W48 to W72: Shift to Abnormal, AE (n=27,24)
    0
    0
        W48 to W84: Shift to Abnormal, not AE (n=6,8)
    0
    1
        W48 to W84: Shift to Abnormal, AE (n=6,8)
    0
    0
        W48 to W96: Shift to Abnormal, not AE (n=3,0)
    0
    0
        W48 to W96: Shift to Abnormal, AE (n=3,0)
    0
    0
        At W60: Normal
    53
    52
        At W60: Abnormal, not AE
    6
    10
        W60 to W72: Shift to Abnormal, not AE (n=26,24)
    1
    2
        W60 to W72: Shift to Abnormal, AE (n=26,24)
    0
    0
        W60 to W84: Shift to Abnormal, not AE (n=6,7)
    0
    2
        W60 to W84: Shift to Abnormal, AE (n=6,7)
    0
    0
        W60 to W96: Shift to Abnormal, not AE (n=2,0)
    0
    0
        W60 to W96: Shift to Abnormal, AE (n=2,0)
    0
    0
        At W72: Normal
    26
    24
        At W72: Abnormal, not AE
    2
    4
        W72 to W84: Shift to Abnormal, not AE (n=5,7)
    0
    1
        W72 to W84: Shift to Abnormal, AE (n=5,7)
    0
    0
        W72 to W96: Shift to Abnormal, not AE (n=2,0)
    0
    0
        W72 to W96: Shift to Abnormal, AE (n=2,0)
    0
    0
        At W84: Normal
    7
    7
        At W84: Abnormal, not AE
    0
    3
        W84 to W96: Shift to Abnormal, not AE (n=3,0)
    0
    0
        W84 to W96: Shift to Abnormal, AE (n=3,0)
    0
    0
        At W96: Normal
    3
    0
        At W96: Abnormal, not AE
    0
    1
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with Potentially Clinically Significant Abnormal Vital Signs Values

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    End point title
    		 Part 2: Percentage of Subjects with Potentially Clinically Significant Abnormal Vital Signs Values
    End point description
    Vital sign measurements including temperature, pulse rate (supine), systolic blood pressure (BP) and diastolic (supine) BP were evaluated for safety. Criteria for abnormalities: Temperature: >38 degree celsius (◦C) or >=1 ◦C increase from baseline (BL); Pulse (1): [>100 beats per minute (bpm) or increase from BL of >30 bpm] or (<40 bpm or decrease from BL of >20 bpm); Systolic BP (2): [>160 millimeters of mercury (mmHg)/increase from BL of >40 mmHg] or (<90 mmHg/decrease from BL of >30 mmHg); Diastolic BP (3): (>100 mmHg/increase from BL of >30 mmHg) or (<45 mmHg/decrease from BL of >20 mmHg). Safety population included all subjects who received at least 1 dose of study treatment. Subjects were analysed based on the actual treatment allocation.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    100
    113
    Units: percentage of subjects
    number (not applicable)
        Temperature:>38◦C / >=1◦C Increase From BL
    4
    5
        Pulse: (1)
    22
    25
        Pulse: >100 bpm or >30 bpm increase from BL
    11
    15
        Pulse: <40 bpm or >20 bpm decrease from BL
    13
    11
        Systolic BP: (2)
    8
    10
        Systolic BP: >160 mmHg / >40 mmHg increase from BL
    4
    4
        Systolic BP: <90 mmHg or >30 mmHg decrease from BL
    4
    8
        Diastolic BP: (3)
    13
    9
        Diastolic BP:>100 mmHg/>30 mmHg increase from BL
    3
    4
        Diastolic BP:<45 mmHg/>20 mmHg decrease from BL
    11
    5
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with Potentially Clinically Significant Abnormal Weight Values

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    End point title
    		 Part 2: Percentage of Subjects with Potentially Clinically Significant Abnormal Weight Values
    End point description
    Criteria for abnormality was defined as a >7% increase or decrease in weight at the specified time point. Safety population included all subjects who received at least 1 dose of study treatment. Subjects were analysed based on the actual treatment allocation. 'Number analysed (n)’ signifies number of subjects analysed at the specified timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline, Week 12, 24, 36, 48, 72 and 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    100
    113
    Units: percentage of subjects
    number (not applicable)
        At Baseline with Increase >7% (n=97,112)
    27
    15
        At Baseline with Decrease >7% (n=97,112)
    4
    15
        At Week 12 with Increase >7% (n=89,101)
    4
    3
        At Week 12 with Decrease >7% (n=89,101)
    1
    2
        At Week 24 with Increase >7% (n=92,104)
    10
    10
        At Week 24 with Decrease >7% (n=92,104)
    1
    5
        At Week 36 with Increase >7% (n=87,103)
    18
    5
        At Week 36 with Decrease >7% (n=87,103)
    1
    7
        At Week 48 with Increase >7% (n=79,96)
    20
    8
        At Week 48 with Decrease >7% (n=79,96)
    0
    10
        At Week 72 with Increase >7% (n=59,66)
    19
    15
        At Week 72 with Decrease >7% (n=59,66)
    3
    12
        At Week 96 with Increase >7% (n=27,31)
    30
    13
        At Week 96 with Decrease >7% (n=27,31)
    4
    16
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects With Columbia Suicide Severity Rating Scale (C-SSRS) Score at any Post-Baseline Visit

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    End point title
    		 Part 2: Number of Subjects With Columbia Suicide Severity Rating Scale (C-SSRS) Score at any Post-Baseline Visit
    End point description
    C-SSRS systematically assess suicidal ideation (SI) and suicidal behavior (SB) rating scale. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with (w) specific plan and intent and behaviors". The scale identifies specific behaviors ranging from "preparatory acts or behavior" to "suicide" which may be indicative of an individual's intent to complete suicide. Safety population included all subjects who received at least 1 dose of study treatment. Subjects were analysed based on the actual treatment allocation. 'Number analysed (n)’ signifies number of subjects analysed for this endpoint. w/o = without
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Week 96
    End point values
    		 Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg
    Number of subjects analysed
    100
    113
    Units: subjects
        SI: Wish to be Dead (n=98,113)
    2
    3
        SI:Non-specific Active Suicidal Thoughts(n=98,113)
    0
    1
        SI: SI w Methods(not Plan) w/o Intent(n=98,113)
    0
    1
        SI: SI w Some Intent, w/o Specific Plan (n=98,113)
    0
    1
        SI: Active SI w Specific Plan and Intent(n=98,113)
    0
    1
        SB: Preparatory Acts or Behavior (n=98,113)
    0
    1
        SB: Aborted Attempt (n=98,113)
    0
    1
        SB: Interrupted Attempt (n=98,113)
    0
    1
        SB: Actual Attempt (n=98,113)
    0
    1
        SB: Suicidal Behavior (n=98,113)
    0
    1
        SB: Suicide (n=97,112)
    0
    0
        Self-injurious Behavior w/o Intent (n=98,113)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: From first dose through 12 weeks after administration of the last dose of study treatment (Up to Week 84); Part 2: From first dose through 12 weeks after administration of the last dose of study treatment (Up to Week 169)
    Adverse event reporting additional description
    Safety population included all subjects who received at least 1 dose of study treatment. Subjects were analysed based on the actual treatment allocation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Subjects with RMS received placebo IV as an add-on therapy to a background DMT once every 4 weeks over 72 weeks.

    Reporting group title
    Part 2: Placebo to BIIB033 750 mg
    Reporting group description
    		 Subjects who received placebo and completed Part 1 were enrolled into Part 2 to receive BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks for up to a maximum of 80 weeks.

    Reporting group title
    Part 2: BIIB033 750 mg
    Reporting group description
    		 Subjects who received BIIB033 and completed Part 1 were enrolled into Part 2 to receive BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks for up to a maximum of 77 weeks.

    Reporting group title
    Part 1: BIIB033 750 mg
    Reporting group description
    		 Subjects with RMS received BIIB033 750 mg IV as an add-on therapy to a background DMT once every 4 weeks over 72 weeks.

    Serious adverse events
    		 Part 1: Placebo Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg Part 1: BIIB033 750 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 131 (4.58%)
    9 / 100 (9.00%)
    2 / 113 (1.77%)
    9 / 132 (6.82%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia stage 1
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    1 / 113 (0.88%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Congenital anomaly
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Meningocele acquired
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Coeliac artery compression syndrome
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol use disorder
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    1 / 113 (0.88%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 100 (1.00%)
    0 / 113 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Placebo Part 2: Placebo to BIIB033 750 mg Part 2: BIIB033 750 mg Part 1: BIIB033 750 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 131 (69.47%)
    34 / 100 (34.00%)
    46 / 113 (40.71%)
    93 / 132 (70.45%)
    Investigations
    Weight increased
         subjects affected / exposed
    3 / 131 (2.29%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    8 / 132 (6.06%)
         occurrences all number
    3
    0
    0
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 131 (9.16%)
    4 / 100 (4.00%)
    8 / 113 (7.08%)
    17 / 132 (12.88%)
         occurrences all number
    22
    8
    8
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 131 (6.87%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    5 / 132 (3.79%)
         occurrences all number
    9
    0
    0
    6
    Headache
         subjects affected / exposed
    23 / 131 (17.56%)
    11 / 100 (11.00%)
    9 / 113 (7.96%)
    19 / 132 (14.39%)
         occurrences all number
    61
    20
    12
    29
    Multiple sclerosis relapse
         subjects affected / exposed
    20 / 131 (15.27%)
    12 / 100 (12.00%)
    13 / 113 (11.50%)
    23 / 132 (17.42%)
         occurrences all number
    25
    15
    14
    29
    Paraesthesia
         subjects affected / exposed
    8 / 131 (6.11%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    7 / 132 (5.30%)
         occurrences all number
    14
    0
    0
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 131 (10.69%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    14 / 132 (10.61%)
         occurrences all number
    19
    0
    0
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 131 (8.40%)
    3 / 100 (3.00%)
    6 / 113 (5.31%)
    6 / 132 (4.55%)
         occurrences all number
    11
    3
    6
    6
    Nausea
         subjects affected / exposed
    10 / 131 (7.63%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    11 / 132 (8.33%)
         occurrences all number
    14
    0
    0
    14
    Vomiting
         subjects affected / exposed
    7 / 131 (5.34%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    4 / 132 (3.03%)
         occurrences all number
    7
    0
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 131 (6.11%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    9 / 132 (6.82%)
         occurrences all number
    8
    0
    0
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 131 (7.63%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    8 / 132 (6.06%)
         occurrences all number
    12
    0
    0
    8
    Back pain
         subjects affected / exposed
    8 / 131 (6.11%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    8 / 132 (6.06%)
         occurrences all number
    11
    0
    0
    10
    Muscle spasms
         subjects affected / exposed
    7 / 131 (5.34%)
    5 / 100 (5.00%)
    0 / 113 (0.00%)
    2 / 132 (1.52%)
         occurrences all number
    7
    5
    0
    2
    Pain in extremity
         subjects affected / exposed
    7 / 131 (5.34%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    10 / 132 (7.58%)
         occurrences all number
    9
    0
    0
    16
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 131 (4.58%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    10 / 132 (7.58%)
         occurrences all number
    7
    0
    0
    12
    Nasopharyngitis
         subjects affected / exposed
    30 / 131 (22.90%)
    4 / 100 (4.00%)
    7 / 113 (6.19%)
    26 / 132 (19.70%)
         occurrences all number
    44
    4
    7
    37
    Sinusitis
         subjects affected / exposed
    5 / 131 (3.82%)
    0 / 100 (0.00%)
    0 / 113 (0.00%)
    9 / 132 (6.82%)
         occurrences all number
    6
    0
    0
    9
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 131 (15.27%)
    5 / 100 (5.00%)
    9 / 113 (7.96%)
    31 / 132 (23.48%)
         occurrences all number
    29
    6
    11
    42
    Urinary tract infection
         subjects affected / exposed
    19 / 131 (14.50%)
    6 / 100 (6.00%)
    10 / 113 (8.85%)
    18 / 132 (13.64%)
         occurrences all number
    33
    6
    11
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2017
    Updated the safety reporting sections of the protocol for accurate representation of serious adverse event (SAE) and suspected unexpected serious adverse reaction reporting responsibilities.
    13 Feb 2019
    Added an optional open-label extension (OLE) phase (Part 2) that will investigate the long-term safety and efficacy of BIIB033 treatment as an add-on therapy to anti-inflammatory DMT for approximately 2 years (96 weeks).

    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.
    The top-line results from the Part 1 did not meet the pre-specified primary endpoint nor the key secondary endpoints. The decision to discontinue study 215MS202 Part 2 was not based on safety concerns.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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