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    Clinical Trial Results:
    A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group, Dose-Ranging Study to Evaluate the Safety and Efficacy of Intravenous Natalizumab (BG00002) in Acute Ischemic Stroke

    Summary
    EudraCT number
    		 2015-004783-11
    Trial protocol
    		 ES   DE   GB  
    Global end of trial date
    20 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2018
    First version publication date
    14 Nov 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    101SK202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02730455
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 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
    20 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the clinical effects of natalizumab versus placebo in acute ischemic stroke on clinical measures of functional independence and activities of daily living.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations 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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 83
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    Spain: 88
    Country: Number of subjects enrolled
    Germany: 82
    Worldwide total number of subjects
    277
    EEA total number of subjects
    194
    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)
    104
    From 65 to 84 years
    173
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 19 sites in Germany, 4 sites in the United Kingdom (UK), 12 sites in Spain, and 18 sites in the United States (US).

    Pre-assignment
    Screening details
    		 A total of 277 subjects with acute ischemic stroke were randomised into the study (94 subjects in the placebo group, 91 subjects in the natalizumab 300 mg group, and 92 subjects in the natalizumab 600 mg group).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV dose of matching placebo to natalizumab on Day 1

    Arm title
    		 Natalizumab 300 mg IV
    Arm description
    		 Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV dose of 300 mg natalizumab on Day 1

    Arm title
    		 Natalizumab 600 mg IV
    Arm description
    		 Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV dose of 600 mg natalizumab on Day 1

    Number of subjects in period 1
    		Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Started
    94
    91
    92
    Safety population
    91
    90
    89
    Subjects dosed
    91
    88
    91
    Who received total volume of study drug
    90
    88
    89
    Completed
    81
    77
    81
    Not completed
    13
    14
    11
         Death
    5
    6
    4
         Other
    1
    1
    2
         Unknown
    2
    2
    -
         Lost to follow-up
    3
    1
    4
         Consent withdrawn
    2
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).

    Reporting group title
    Natalizumab 300 mg IV
    Reporting group description
    		 Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).

    Reporting group title
    Natalizumab 600 mg IV
    Reporting group description
    		 Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).

    Reporting group values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV Total
    Number of subjects
    		 94 91 92 277
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.1 ( 9.54 ) 66.1 ( 10.47 ) 65.6 ( 11.09 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 29 36 37 102
        Male
    		 65 55 55 175
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 3 7
        Not Hispanic or Latino
    		 28 24 24 76
        Unknown or Not Reported
    		 64 65 65 194
    Race
    Units: Subjects
        Black or African American
    		 2 1 1 4
        White
    		 27 25 25 77
        Not Reported Due to Confidentiality Regulations
    		 64 65 65 194
        Missing
    		 1 0 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).

    Reporting group title
    Natalizumab 300 mg IV
    Reporting group description
    		 Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).

    Reporting group title
    Natalizumab 600 mg IV
    Reporting group description
    		 Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the subject was last known normal (LKN).

    Primary: Percentage of Subjects With Composite Global Measure of Functional Disability Based at Day 90

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    End point title
    		 Percentage of Subjects With Composite Global Measure of Functional Disability Based at Day 90
    End point description
    The composite global measure of functional disability excellent outcome was based on a score of 0 or 1 on the modified Rankin Scale (mRS) and a score of >=95 on the Barthel Index (BI). mRS measures independence, rather than neurological function, with specific tasks pre- and post-stroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. BI consists of 10 items that measure a subject’s daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. Scores for each of the items are summed to create a total score of 0 to 100. Higher the score, more “independent” the subject is. Modified Intent-to-Treat (MITT) population. N=subjects evaluable with data available for analysis.
    End point type
    Primary
    End point timeframe
    Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    90
    88
    89
    Units: percentage of subjects
        number (not applicable)
    54.1
    41.5
    39.9
    Statistical analysis title
    		 Placebo vs Natalizumab 300 mg IV
    Statistical analysis description
    Composite Measure: The global odds ratio was based on a linear logistic regression model with baseline National Institute of Health Stroke Scale (NIHSS) category (score 5-15, 16-23), age (<60, 60-69, 70-80), tissue plasminogen activator (tPA) use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, United States of America [USA]) as covariates and unstructured working correlation structure
    Comparison groups
    Placebo v Natalizumab 300 mg IV
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.086
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.07
    Statistical analysis title
    		 Placebo vs Natalizumab 600 mg IV
    Statistical analysis description
    Composite Measure: The global odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure
    Comparison groups
    Placebo v Natalizumab 600 mg IV
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.95

    Secondary: Percentage of Subjects With Excellent Outcome in mRS Score at Day 90

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    End point title
    		 Percentage of Subjects With Excellent Outcome in mRS Score at Day 90
    End point description
    Excellent mRS is defined as mRS score of 0 or 1. mRS measures independence, rather than neurological function, with specific tasks pre- and poststroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. MITT population: all randomised subjects who had received entire infusion of study treatment. Subjects who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number of subject analysed is number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    86
    83
    82
    Units: percentage of subjects
        number (not applicable)
    41
    29
    26
    Statistical analysis title
    		 mRS Score: Placebo vs Natalizumab 300 mg IV
    Statistical analysis description
    The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure.
    Comparison groups
    Placebo v Natalizumab 300 mg IV
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.222
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.28
    Statistical analysis title
    		 mRS Score: Placebo vs Natalizumab 600 mg IV
    Statistical analysis description
    The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure.
    Comparison groups
    Placebo v Natalizumab 600 mg IV
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.06

    Secondary: Percentage of Subjects With Excellent Outcome in BI Score at Day 90

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    End point title
    		 Percentage of Subjects With Excellent Outcome in BI Score at Day 90
    End point description
    Excellent BI outcome is defined as a score of >=95. BI consists of 10 items that measure a subject’s daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more “independent” the subject is. MITT population: all randomised subjects who had received entire infusion of study treatment. Subjects who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number of subject analysed is number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    86
    81
    81
    Units: percentage of subjects
        number (not applicable)
    67
    54
    54
    Statistical analysis title
    		 BI Score: Placebo vs Natalizumab 300 mg IV
    Statistical analysis description
    The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure.
    Comparison groups
    Placebo v Natalizumab 300 mg IV
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.08
    Statistical analysis title
    		 BI Score: Placebo vs Natalizumab 600 mg IV
    Statistical analysis description
    The odds ratio was based on a linear logistic regression model with baseline NIHSS category (score 5-15, 16-23), age (<60, 60-69, 70-80), tPA use (yes/no), treatment window (<=9, >9 and <=24hours), thrombectomy (yes/no) and region (Spain, UK/Germany, USA) as covariates and unstructured working correlation structure.
    Comparison groups
    Placebo v Natalizumab 600 mg IV
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.067
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.04

    Secondary: Stroke Impact Scale-16 (SIS-16) Score Using a Repeated Measures Mixed Effects Model at Day 90

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    End point title
    		 Stroke Impact Scale-16 (SIS-16) Score Using a Repeated Measures Mixed Effects Model at Day 90
    End point description
    The SIS-16 is a 16-item physical dimension instrument that was developed as a brief, stand-alone tool for measuring the physical aspects of stroke recovery. The 16 physical aspects are rated on a 1 to 5 scale as follows: not difficult at all (5), a little difficult (4), somewhat difficult (3), very difficult (2), and could not do at all (1). Total score range is 16 to 80, with higher scores indicating higher levels of health-related quality of life and function. MITT population: all randomised subjects who had received entire infusion of study treatment. Subjects who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number of subject analysed is number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    84
    80
    77
    Units: score on a scale
        arithmetic mean (standard deviation)
    76.21 ( 30.783 )
    66.96 ( 35.493 )
    68.10 ( 31.461 )
    Statistical analysis title
    		 SIS-16 Score: Placebo vs Natalizumab 300 mg IV
    Statistical analysis description
    Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
    Comparison groups
    Placebo v Natalizumab 300 mg IV
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.106
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.97
         upper limit
    		 1.64
    Statistical analysis title
    		 SIS-16 Score: Placebo vs Natalizumab 600 mg IV
    Statistical analysis description
    Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
    Comparison groups
    Placebo v Natalizumab 600 mg IV
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.202
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.43
         upper limit
    		 3.27

    Secondary: Montreal Cognitive Assessment (MoCA) Score at Day 90

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    End point title
    		 Montreal Cognitive Assessment (MoCA) Score at Day 90
    End point description
    The MoCA is a global cognitive screening test with favorable psychometric properties It screens 8 domains: visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 0 to 30 points; a score of 26 or above is considered normal, <10 (severe cognitive impairment), 10-17 (moderate cognitive impairment) and >=18 (mild cognitive impairment). MITT population: all randomised subjects who had received entire infusion of study treatment. Subjects who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analysed is number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    69
    74
    69
    Units: scores on a scale
        arithmetic mean (standard deviation)
    21.23 ( 8.412 )
    20.73 ( 8.141 )
    20.90 ( 8.223 )
    Statistical analysis title
    		 MoCA: Palcebo vs Natalizumab 300 mg IV
    Statistical analysis description
    Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
    Comparison groups
    Placebo v Natalizumab 300 mg IV
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.64
         upper limit
    		 1.99
    Statistical analysis title
    		 MoCA: Placebo vs Natalizumab 600 mg IV
    Statistical analysis description
    Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
    Comparison groups
    Placebo v Natalizumab 600 mg IV
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.622
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.89
         upper limit
    		 1.73

    Secondary: Change From Baseline in National Institute of Health Stroke Scale (NIHSS) Score at Day 90

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    End point title
    		 Change From Baseline in National Institute of Health Stroke Scale (NIHSS) Score at Day 90
    End point description
    The NIHSS is a reliable tool for rapidly evaluating the effects of acute cerebral infarction. A trained observer rates the subject’s ability to answer questions and perform activities relating to level of consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, sensory loss, and extinction and inattention (formerly neglect). There are 15 items. Total score ranges from 0 as normal to a maximum possible total severity score of 42 for all items. Higher the score, more the severity. A negative change from Baseline indicates improvement. MITT population: all randomised subjects who had received entire infusion of study treatment. Subjects who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number of subject analysed is number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    77
    76
    71
    Units: score on a scale
        arithmetic mean (standard deviation)
    -6.14 ( 6.920 )
    -5.17 ( 7.937 )
    -6.28 ( 6.510 )
    Statistical analysis title
    		 Placebo vs Natalizumab 300 mg IV
    Statistical analysis description
    Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
    Comparison groups
    Placebo v Natalizumab 300 mg IV
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.315
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 3.4
    Statistical analysis title
    		 Placebo vs Natalizumab 600 mg IV
    Statistical analysis description
    Treatment and treatment by visit interaction were included in the model as explanatory variables. Baseline NIHSS category (score 5-15, 16-23), tPA use (yes/no), age (<60, 60-69, 70-80), thrombectomy (yes/no), region (Spain, UK/Germany, USA) and treatment window were considered as covariates. An unstructured variance-covariance matrix was used in the model.
    Comparison groups
    Placebo v Natalizumab 600 mg IV
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.542
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.96
         upper limit
    		 1.56

    Secondary: Number of Subjects Experiencing Adverse Events (AE)

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    End point title
    		 Number of Subjects Experiencing Adverse Events (AE)
    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. The safety population was defined as subjects who had received any study treatment, including cases of complete or incomplete infusion.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    91
    90
    89
    Units: subjects
    84
    81
    82
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing Serious Adverse Events (SAE)

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    End point title
    		 Number of Subjects Experiencing Serious Adverse Events (SAE)
    End point description
    A SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization, results in a significant disability/incapacity or congenital anomaly. The safety population was defined as subjects who had received any study treatment, including cases of complete or incomplete infusion.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    91
    90
    89
    Units: subjects
    19
    23
    29
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Dose Response at Day 90

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    End point title
    		 Percentage of Subjects With Dose Response at Day 90
    End point description
    Percentage of subjects with dose response was evaluated in proportion of excellent outcome on mRS and BI. MITT population: all randomised subjects who had received entire infusion of study treatment. Subjects who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. n specifies number of subjects evaluate for specific categories.
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Placebo Natalizumab 300 mg IV Natalizumab 600 mg IV
    Number of subjects analysed
    90
    88
    89
    Units: percentage of subjects
    number (not applicable)
        mRS (0, 1), n= 86, 83, 82
    41
    29
    26
        BI (>=95), n= 86, 81, 81
    67
    54
    54
    Statistical analysis title
    		 Dose response in proportion of mRS
    Statistical analysis description
    mRS: The Cochran-Armitage trend test of a monotonically increasing dose response in a proportion of excellent outcome. Dose levels are log transformed.
    Comparison groups
    Placebo v Natalizumab 300 mg IV v Natalizumab 600 mg IV
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028
    Method
    		 Cochran-Armitage trend test
    Confidence interval
    Statistical analysis title
    		 Dose response in proportion of BI
    Statistical analysis description
    BI: The Cochran-Armitage trend test of a monotonically increasing dose response in a proportion of excellent outcome. Dose levels are log transformed
    Comparison groups
    Placebo v Natalizumab 300 mg IV v Natalizumab 600 mg IV
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Cochran-Armitage trend test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 90
    Adverse event reporting additional description
    The safety population was defined as subjects who had received any study treatment, including cases of complete or incomplete infusion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours of last known normal (LKN) or between 9-24 hours after LKN.

    Reporting group title
    Natalizumab 600 mg IV
    Reporting group description
    		 Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours of LKN or between 9-24 hours after LKN.

    Reporting group title
    Natalizumab 300 mg IV
    Reporting group description
    		 Single 300 milligram (mg) natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours of LKN or between 9-24 hours after LKN.

    Serious adverse events
    		 Placebo Natalizumab 600 mg IV Natalizumab 300 mg IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 91 (20.88%)
    29 / 89 (32.58%)
    23 / 90 (25.56%)
         number of deaths (all causes)
    5
    4
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma stage IV
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Aortic embolus
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 91 (1.10%)
    2 / 89 (2.25%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    Pneumothorax
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 91 (0.00%)
    3 / 89 (3.37%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 91 (1.10%)
    2 / 89 (2.25%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Investigations
    Escherichia test positive
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Aortic restenosis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprocedural myocardial infarction
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Post procedural complication
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Wound dehiscence
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 91 (1.10%)
    2 / 89 (2.25%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral artery occlusion
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 89 (2.25%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 91 (1.10%)
    2 / 89 (2.25%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Cerebral reperfusion injury
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 91 (2.20%)
    3 / 89 (3.37%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytotoxic oedema
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 89 (2.25%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lacunar infarction
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer haemorrhage
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Idiopathic angioedema
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 89 (2.25%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric rupture
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Endocarditis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 91 (2.20%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia acinetobacter
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 91 (2.20%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Septic encephalopathy
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Splenic abscess
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Natalizumab 600 mg IV Natalizumab 300 mg IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 91 (73.63%)
    65 / 89 (73.03%)
    69 / 90 (76.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 91 (6.59%)
    8 / 89 (8.99%)
    7 / 90 (7.78%)
         occurrences all number
    6
    9
    7
    Hypotension
         subjects affected / exposed
    5 / 91 (5.49%)
    7 / 89 (7.87%)
    4 / 90 (4.44%)
         occurrences all number
    5
    7
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 91 (5.49%)
    1 / 89 (1.12%)
    1 / 90 (1.11%)
         occurrences all number
    5
    1
    1
    Pain
         subjects affected / exposed
    3 / 91 (3.30%)
    2 / 89 (2.25%)
    7 / 90 (7.78%)
         occurrences all number
    3
    3
    8
    Pyrexia
         subjects affected / exposed
    11 / 91 (12.09%)
    14 / 89 (15.73%)
    19 / 90 (21.11%)
         occurrences all number
    11
    21
    24
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    5 / 91 (5.49%)
    1 / 89 (1.12%)
    5 / 90 (5.56%)
         occurrences all number
    5
    1
    5
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    8 / 91 (8.79%)
    0 / 89 (0.00%)
    5 / 90 (5.56%)
         occurrences all number
    8
    0
    5
    Anxiety
         subjects affected / exposed
    4 / 91 (4.40%)
    7 / 89 (7.87%)
    2 / 90 (2.22%)
         occurrences all number
    4
    7
    2
    Depression
         subjects affected / exposed
    16 / 91 (17.58%)
    10 / 89 (11.24%)
    13 / 90 (14.44%)
         occurrences all number
    16
    10
    13
    Insomnia
         subjects affected / exposed
    4 / 91 (4.40%)
    10 / 89 (11.24%)
    11 / 90 (12.22%)
         occurrences all number
    4
    11
    11
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 91 (5.49%)
    5 / 89 (5.62%)
    7 / 90 (7.78%)
         occurrences all number
    5
    5
    7
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 91 (8.79%)
    7 / 89 (7.87%)
    6 / 90 (6.67%)
         occurrences all number
    8
    8
    6
    Nervous system disorders
    Haemorrhagic transformation stroke
         subjects affected / exposed
    4 / 91 (4.40%)
    5 / 89 (5.62%)
    4 / 90 (4.44%)
         occurrences all number
    4
    5
    4
    Headache
         subjects affected / exposed
    15 / 91 (16.48%)
    20 / 89 (22.47%)
    16 / 90 (17.78%)
         occurrences all number
    18
    22
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 91 (3.30%)
    5 / 89 (5.62%)
    3 / 90 (3.33%)
         occurrences all number
    3
    6
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
    5 / 90 (5.56%)
         occurrences all number
    1
    1
    5
    Constipation
         subjects affected / exposed
    18 / 91 (19.78%)
    23 / 89 (25.84%)
    19 / 90 (21.11%)
         occurrences all number
    21
    30
    22
    Diarrhoea
         subjects affected / exposed
    4 / 91 (4.40%)
    3 / 89 (3.37%)
    5 / 90 (5.56%)
         occurrences all number
    5
    3
    5
    Dysphagia
         subjects affected / exposed
    1 / 91 (1.10%)
    2 / 89 (2.25%)
    6 / 90 (6.67%)
         occurrences all number
    1
    2
    6
    Nausea
         subjects affected / exposed
    4 / 91 (4.40%)
    6 / 89 (6.74%)
    7 / 90 (7.78%)
         occurrences all number
    5
    7
    7
    Vomiting
         subjects affected / exposed
    3 / 91 (3.30%)
    1 / 89 (1.12%)
    7 / 90 (7.78%)
         occurrences all number
    3
    1
    8
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 91 (5.49%)
    3 / 89 (3.37%)
    3 / 90 (3.33%)
         occurrences all number
    5
    3
    3
    Urinary retention
         subjects affected / exposed
    6 / 91 (6.59%)
    3 / 89 (3.37%)
    4 / 90 (4.44%)
         occurrences all number
    6
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 91 (0.00%)
    5 / 89 (5.62%)
    1 / 90 (1.11%)
         occurrences all number
    0
    6
    1
    Pain in extremity
         subjects affected / exposed
    2 / 91 (2.20%)
    2 / 89 (2.25%)
    5 / 90 (5.56%)
         occurrences all number
    2
    2
    8
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 91 (3.30%)
    8 / 89 (8.99%)
    2 / 90 (2.22%)
         occurrences all number
    3
    9
    2
    Urinary tract infection
         subjects affected / exposed
    11 / 91 (12.09%)
    15 / 89 (16.85%)
    14 / 90 (15.56%)
         occurrences all number
    13
    18
    16
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    6 / 91 (6.59%)
    6 / 89 (6.74%)
    12 / 90 (13.33%)
         occurrences all number
    6
    7
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2016
    • The protocol was amended to remove unnecessary study procedures (i.e., 0 hour blood draw and the Functional Independence Measure at Day 5) and to add an expanded treatment window (>9 to ≤24 hours) in which subjects would be eligible for inclusion in the study. • An NIHSS screening score for eligibility was added to the inclusion criteria for the >9 to ≤24 hour treatment window, and NIHSS eligibility was to be confirmed within 60 minutes prior to randomization. • Exclusion criteria were updated to clarify that the subjects with rapidly improving or minor stroke symptoms, or with petechial hemorrhages ≤1 centimeter (cm) were no longer excluded from the study. • The statement regarding performing brain Magnetic resonance imaging (MRI) to assess subject eligibility was removed from the exclusion criteria, and the types of exclusionary strokes were clarified. • The exclusion criteria regarding hepatitis infections and bacterial, fungal, or viral infections were simplified. • It was clarified that thrombolytic treatments/procedures would be recorded as concomitant regardless of whether they were given before or after informed consent. • Contraception language was updated so that all subjects were instructed to use highly effective methods of contraception and so that the methods of highly effective contraception were defined consistently with the Clinical Trial Facilitation Group’s recommendations. • The sample size was increased from 225 to 270 to account for the addition of a new treatment window (>9 to ≤24 hours from LKN).
    03 May 2017
    • The protocol was amended to correct an error in the pharmacokinetic (PK)/pharmacodynamic (PD) sampling times. It was clarified that the blood samples for PK/PD assessments, as well as vital sign measurements, were taken within 1 hour after the infusion had stopped.

    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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