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

    Summary
    EudraCT number
    2013-001514-15
    Trial protocol
    DE   ES  
    Global end of trial date
    09 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Apr 2016
    First version publication date
    15 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    101SK201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01955707
    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
    09 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine whether one 300-mg dose of intravenous (IV) natalizumab reduces the change in infarct volume from Baseline to Day 5 on magnetic resonance imaging (MRI) in subjects with acute ischemic stroke when given at ≤ 6 hours or at > 6 to ≤ 9 hours from when they were last known normal (LKN). The secondary objectives of this study in this study population are as follows: to assess the efficacy of natalizumab on change in infarct volume from Baseline to Day 30; to assess efficacy of natalizumab on change in infarct volume from 24 hours to Day 5 and Day 30; to assess the efficacy of natalizumab on clinical measures of stroke outcome; and to assess the safety of natalizumab in subjects with acute ischemic stroke.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason. Subjects were observed for 1 hour after the study treatment infusion to allow monitoring for hypersensitivity reactions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 62
    Country: Number of subjects enrolled
    United States: 42
    Country: Number of subjects enrolled
    Germany: 57
    Worldwide total number of subjects
    161
    EEA total number of subjects
    119
    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)
    37
    From 65 to 84 years
    118
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject eligibility for the study was determined at the time of acute ischemic stroke diagnosis.

    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
    Blinding implementation details
    This was a randomized, double-blind, placebo-controlled study. Subjects and all study staff, including the Pharmacist, were blinded to the subject treatment assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    A single IV injection of placebo
    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
    All subjects with acute ischemic stroke will receive an infusion of blinded study treatment at ≤ 6 hours or at > 6 to ≤ 9 hours from when they were LKN.

    Arm title
    Natalizumab
    Arm description
    300-mg single IV injection of natalizumab
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects with acute ischemic stroke will receive an infusion of blinded study treatment at ≤ 6 hours or at > 6 to ≤ 9 hours from when they were LKN.

    Number of subjects in period 1
    Placebo Natalizumab
    Started
    82
    79
    Withdrew Prior to Dosing
    0 [1]
    1 [2]
    Dosed
    82
    78
    Received Total Volume of Study Drug
    82
    77
    Completed
    62
    57
    Not completed
    20
    22
         Death
    13
    14
         Adverse event
    1
    2
         Not specified
    4
    2
         Consent withdrawn by subject
    -
    3
         Lost to follow-up
    2
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones follow the correct flow of subjects through the study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones follow the correct flow of subjects through the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    A single IV injection of placebo

    Reporting group title
    Natalizumab
    Reporting group description
    300-mg single IV injection of natalizumab

    Reporting group values
    Placebo Natalizumab Total
    Number of subjects
    82 79 161
    Age categorical
    Units: Subjects
        </= 39 years
    2 3 5
        40 to 59 years
    13 11 24
        60 to 79 years
    41 45 86
        >/= 80 years
    26 20 46
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.6 ± 11.83 70.3 ± 13.34 -
    Gender categorical
    Units: Subjects
        Female
    34 38 72
        Male
    48 41 89

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    A single IV injection of placebo

    Reporting group title
    Natalizumab
    Reporting group description
    300-mg single IV injection of natalizumab

    Subject analysis set title
    Modified intention to treat: Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects who were randomized to placebo and received the entire infusion of study treatment.

    Subject analysis set title
    Modified intention to treat: Natalizumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects who were randomized to natalizumab and received the entire infusion of study treatment.

    Subject analysis set title
    Safety population: Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who were randomized to placebo and received any portion of the infusion of study treatment.

    Subject analysis set title
    Safety population: Natalizumab
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who were randomized to natalizumab and received any portion of the infusion of study treatment.

    Primary: Change in Infarct Volume From Baseline (Diffusion-Weighted Imaging [DWI]) to Day 5 (Fluid-Attenuated Inversion Recovery [FLAIR])

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    End point title
    Change in Infarct Volume From Baseline (Diffusion-Weighted Imaging [DWI]) to Day 5 (Fluid-Attenuated Inversion Recovery [FLAIR])
    End point description
    Relative growth of infarct volume from Baseline (relative growth = FLAIR at Day 5 divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
    End point type
    Primary
    End point timeframe
    Baseline, Day 5
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    73
    69
    Units: mL
        geometric mean (inter-quartile range (Q1-Q3))
    2.17 (1.6 to 3.17)
    2.37 (1.51 to 2.91)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to baseline using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tissue plasminogen activator (tPA) use.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    adjusted mean difference (log-scale)
    Point estimate
    0.08
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.09
         upper limit
    0.26
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.779 [1]
    Method
    repeated measures mixed effects model
    Parameter type
    ratio of relative growth
    Point estimate
    1.09
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.3
    Notes
    [1] - one-sided p-value

    Secondary: Change in Infarct Volume From Baseline (DWI) to 24 Hours (FLAIR)

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    End point title
    Change in Infarct Volume From Baseline (DWI) to 24 Hours (FLAIR)
    End point description
    Relative growth of infarct volume from Baseline (relative growth = FLAIR at 24 hours divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 hrs
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    74 [2]
    69 [3]
    Units: mL
        geometric mean (inter-quartile range (Q1-Q3))
    1.73 (1.33 to 2.15)
    1.95 (1.36 to 2.2)
    Notes
    [2] - subjects with assessments at both time points
    [3] - subjects with assessments at both time points
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to baseline using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    adjusted mean difference (log-scale)
    Point estimate
    0.09
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.09
         upper limit
    0.27
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.797 [4]
    Method
    repeated measures mixed effects model
    Parameter type
    ratio of relative growth
    Point estimate
    1.09
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.31
    Notes
    [4] - one-sided p-value

    Secondary: Change in Infarct Volume From Baseline (DWI) to Day 30 (FLAIR)

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    End point title
    Change in Infarct Volume From Baseline (DWI) to Day 30 (FLAIR)
    End point description
    Relative growth of infarct volume from Baseline (relative growth = FLAIR at Day 30 divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    66 [5]
    55 [6]
    Units: mL
        geometric mean (inter-quartile range (Q1-Q3))
    1.27 (0.9 to 1.88)
    1.25 (0.78 to 1.93)
    Notes
    [5] - subjects with assessments at both time points.
    [6] - subjects with assessments at both time points.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to baseline using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    adjusted mean difference (log-scale)
    Point estimate
    0.05
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.13
         upper limit
    0.24
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.684 [7]
    Method
    repeated measures mixed effects model
    Parameter type
    ratio of relative growth
    Point estimate
    1.05
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.27
    Notes
    [7] - one-sided p-value

    Secondary: Change in Infarct Volume From 24 Hours (FLAIR) to Day 5 (FLAIR)

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    End point title
    Change in Infarct Volume From 24 Hours (FLAIR) to Day 5 (FLAIR)
    End point description
    Relative growth of infarct volume from 24 hours (relative growth = FLAIR at Day 5 divided by FLAIR at 24 hours). Geometric mean calculated as the exponential of the mean log relative growth.
    End point type
    Secondary
    End point timeframe
    24 hours, Day 5
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    70 [8]
    65 [9]
    Units: mL
        geometric mean (inter-quartile range (Q1-Q3))
    1.27 (1.11 to 1.37)
    1.25 (1.11 to 1.42)
    Notes
    [8] - subjects with assessments at both time points.
    [9] - subjects with assessments at both time points.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to 24 hours using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    adjusted mean difference (log-scale)
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.11
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.487 [10]
    Method
    repeated measures mixed effects model
    Parameter type
    ratio of relative growth
    Point estimate
    1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.12
    Notes
    [10] - one-sided p-value

    Secondary: Change in Infarct Volume From 24 Hours (FLAIR) to Day 30 (FLAIR)

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    End point title
    Change in Infarct Volume From 24 Hours (FLAIR) to Day 30 (FLAIR)
    End point description
    Relative growth in infarct volume from 24 hours (relative growth = FLAIR Day 30 divided by FLAIR at 24 hours ). Geometric mean calculated as the exponential of the mean log relative growth.
    End point type
    Secondary
    End point timeframe
    24 hours, Day 30
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    62 [11]
    53 [12]
    Units: mL
        geometric mean (inter-quartile range (Q1-Q3))
    0.75 (0.62 to 1.03)
    0.72 (0.56 to 1.09)
    Notes
    [11] - Subjects with assessments at both time points.
    [12] - Subjects with assessments at both time points.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to 24 hours using an autoregressive variance-covariance matrix structure. The model adjusts for treatment, time, treatment by time, log baseline DWI volume, treatment time window, and tPA use.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    adjusted mean difference (log-scale)
    Point estimate
    -0.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.402 [13]
    Method
    repeated measures mixed effects model
    Parameter type
    ratio of relative growth
    Point estimate
    0.98
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.11
    Notes
    [13] - one-sided p-value

    Secondary: Change in Infarct Volume From Day 5 (FLAIR) to Day 30 (FLAIR)

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    End point title
    Change in Infarct Volume From Day 5 (FLAIR) to Day 30 (FLAIR)
    End point description
    Relative growth of infarct volume from Day 5 (relative growth = FLAIR at Day 30 divided by FLAIR at Day 5). Geometric mean calculated as the exponential of the mean log relative growth.
    End point type
    Secondary
    End point timeframe
    Day 5. Day 30
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    64 [14]
    54 [15]
    Units: mL
        geometric mean (inter-quartile range (Q1-Q3))
    0.6 (0.52 to 0.79)
    0.59 (0.42 to 0.81)
    Notes
    [14] - Subjects with assessments at both time points.
    [15] - Subjects with assessments at both time points.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment contrasts derived from a repeated measures mixed effects model modeling log relative growth relative to Day 5 using an autoregressive variance-covariance matrix structure. The model adjusts for for treatment, log baseline DWI volume, treatment time window, and tPA use.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    adjusted mean difference (log-scale)
    Point estimate
    -0.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.18
         upper limit
    0.13
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted mean (log-scale) back-transformed to the original scale as the estimated ratio of natalizumab to placebo. 90% confidence interval (log-scale) back-transformed to the original scale and reflect the interval around the ratio.
    Comparison groups
    Modified intention to treat: Placebo v Modified intention to treat: Natalizumab
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.394 [16]
    Method
    repeated measures mixed effects model
    Parameter type
    ratio of relative growth
    Point estimate
    0.98
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.14
    Notes
    [16] - one-sided p-value

    Secondary: Change in National Institute of Health Stroke Scale (NIHSS) Score From Baseline to 24 Hours, Day 5, Day 30, and Day 90

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    End point title
    Change in National Institute of Health Stroke Scale (NIHSS) Score From Baseline to 24 Hours, Day 5, Day 30, and Day 90
    End point description
    The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. Scores for the NIHSS range from 0 to 42, with 0 representing no symptoms and 42 representing death.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 hours, Day 5, Day 30, Day 90
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    82 [17]
    77 [18]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change at 24 hours; n=82, 77
    -1.5 ± 3.96
    -1.5 ± 5.1
        Change at Day 5; n=79, 72
    -3.3 ± 5.31
    -2.1 ± 6.24
        Change at Day 30; n=73, 62
    -5.7 ± 5.22
    -4.9 ± 5.73
        Change at Day 90; n=62, 56
    -7.3 ± 3.95
    -6.8 ± 5.78
    Attachments
    NIHSS Statistical Analyses
    Notes
    [17] - n=subjects with assessments at Baseline and given time point.
    [18] - n=subjects with assessments at Baseline and given time point.
    No statistical analyses for this end point

    Secondary: Modified Rankin Scale (mRS) Distribution at Day 5, Day 30, and Day 90

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    End point title
    Modified Rankin Scale (mRS) Distribution at Day 5, Day 30, and Day 90
    End point description
    The mRS measures independence, rather than neurologic function, with specific tasks pre- and post-stroke, respectively. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. The distribution of mRS scores was summarized at each timepoint. An excellent outcome on the mRS was defined as a score of 0 or 1, while a good outcome was defined as a score of 0, 1, or 2.
    End point type
    Secondary
    End point timeframe
    Day 5, Day 30, and Day 90
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    82 [19]
    77 [20]
    Units: subjects
        Day 5: Score 0; n=82, 76
    0
    2
        Day 5: Score 1; n=82, 76
    3
    2
        Day 5: Score 2; n=82, 76
    10
    11
        Day 5: Score 3; n=82, 76
    13
    11
        Day 5: Score 4; n=82, 76
    25
    16
        Day 5: Score 5; n=82, 76
    29
    31
        Day 5: Score 6; n=82, 76
    2
    3
        Day 30: Score 0; n=81, 72
    0
    5
        Day 30: Score 1; n=81, 72
    7
    8
        Day 30: Score 2; n=81, 72
    14
    8
        Day 30: Score 3; n=81, 72
    17
    17
        Day 30: Score 4; n=81, 72
    22
    14
        Day 30: Score 5; n=81, 72
    13
    11
        Day 30: Score 6; n=81, 72
    8
    9
        Day 90: Score 0; n=78, 72
    4
    8
        Day 90: Score 1; n=78, 72
    12
    10
        Day 90: Score 2; n=78, 72
    12
    10
        Day 90: Score 3; n=78, 72
    15
    13
        Day 90: Score 4; n=78, 72
    14
    11
        Day 90: Score 5; n=78, 72
    8
    6
        Day 90: Score 6; n=78, 72
    13
    14
    Attachments
    Untitled (Filename: Statistical Analyses mRS Day 5.pdf)
    Untitled (Filename: Statistical Analyses mRS Day 30.pdf)
    Untitled (Filename: Statistical Analyses mRS Day 90.pdf)
    Notes
    [19] - imputed data; n=number of subjects with an assessment at given time point.
    [20] - imputed data; n=number of subjects with an assessment at given time point.
    No statistical analyses for this end point

    Secondary: Barthel Index at Day 5, Day 30, and Day 90

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    End point title
    Barthel Index at Day 5, Day 30, and Day 90
    End point description
    The Barthel Index consists of 10 items that measure a person’s daily functioning, specifically the activities of daily living and mobility, and can be used to determine a baseline level of functioning and to monitor change in activities of daily living over time. The scores for each of the items are summed to create a total score up to a potential of 100, with higher scores representing a greater level of independence.
    End point type
    Secondary
    End point timeframe
    Day 5, Day 30, and Day 90
    End point values
    Modified intention to treat: Placebo Modified intention to treat: Natalizumab
    Number of subjects analysed
    82 [21]
    77 [22]
    Units: units on a scale
    median (full range (min-max))
        Day 5; n=78, 73
    35 (0 to 100)
    30 (0 to 100)
        Day 30; n=73, 60
    70 (0 to 100)
    80 (0 to 100)
        Day 90; n=61, 55
    80 (0 to 100)
    95 (0 to 100)
    Attachments
    Untitled (Filename: Statistical Analyses Barthel Index.pdf)
    Notes
    [21] - n=subjects with assessment at given time point.
    [22] - n=subjects with assessment at given time point.
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Experience Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects Who Experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    AE: any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as severe, moderate, or mild, and related or not related to study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Day 90 ± 5 days
    End point values
    Safety population: Placebo Safety population: Natalizumab
    Number of subjects analysed
    82
    78
    Units: subjects
        Subjects with an event
    81
    77
        Subjects with a moderate or severe event
    60
    53
        Subjects with a severe event
    27
    22
        Subjects with a related event
    7
    6
        Subjects with a serious event
    38
    36
        Subjects discontinuing due to an event
    0
    0
        Subjects withdrawing from study due to event
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent (SAE) or initiation of study drug (AE) until Final Visit Day 90 ± 5 days or early termination follow-up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    300 mg single IV injection of natalizumab

    Reporting group title
    Placebo
    Reporting group description
    A single IV injection of placebo

    Serious adverse events
    Natalizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 78 (46.15%)
    38 / 82 (46.34%)
         number of deaths (all causes)
    14
    13
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral embolism
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral ischaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Endarterectomy
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Avulsion fracture
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Fall
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulseless electrical activity
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenic haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Nervous system disorders
    Basilar artery thrombosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain midline shift
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Convulsion
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia alzheimer's type
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised non-convulsive epilepsy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Partial seizures
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure chronic
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Toxic nodular goitre
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Natalizumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 78 (87.18%)
    75 / 82 (91.46%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 78 (19.23%)
    10 / 82 (12.20%)
         occurrences all number
    16
    11
    Hypotension
         subjects affected / exposed
    2 / 78 (2.56%)
    12 / 82 (14.63%)
         occurrences all number
    3
    13
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    9 / 78 (11.54%)
    6 / 82 (7.32%)
         occurrences all number
    9
    6
    Pyrexia
         subjects affected / exposed
    32 / 78 (41.03%)
    26 / 82 (31.71%)
         occurrences all number
    34
    30
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    11 / 78 (14.10%)
    3 / 82 (3.66%)
         occurrences all number
    12
    4
    Anxiety
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 82 (1.22%)
         occurrences all number
    6
    1
    Depression
         subjects affected / exposed
    5 / 78 (6.41%)
    13 / 82 (15.85%)
         occurrences all number
    5
    14
    Insomnia
         subjects affected / exposed
    7 / 78 (8.97%)
    13 / 82 (15.85%)
         occurrences all number
    7
    13
    Sleep disorder
         subjects affected / exposed
    8 / 78 (10.26%)
    7 / 82 (8.54%)
         occurrences all number
    10
    7
    Post stroke depression
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 82 (2.44%)
         occurrences all number
    4
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 78 (10.26%)
    4 / 82 (4.88%)
         occurrences all number
    9
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 82 (1.22%)
         occurrences all number
    5
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 82 (2.44%)
         occurrences all number
    4
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 82 (6.10%)
         occurrences all number
    4
    5
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    7 / 78 (8.97%)
    10 / 82 (12.20%)
         occurrences all number
    7
    10
    Bradycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    5 / 82 (6.10%)
         occurrences all number
    1
    6
    Tachycardia
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 82 (6.10%)
         occurrences all number
    3
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 78 (10.26%)
    4 / 82 (4.88%)
         occurrences all number
    9
    5
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 82 (3.66%)
         occurrences all number
    6
    3
    Cerebral haemorrhage
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 82 (0.00%)
         occurrences all number
    4
    0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    18 / 78 (23.08%)
    21 / 82 (25.61%)
         occurrences all number
    18
    21
    Headache
         subjects affected / exposed
    13 / 78 (16.67%)
    19 / 82 (23.17%)
         occurrences all number
    13
    21
    Somnolence
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 82 (3.66%)
         occurrences all number
    4
    3
    Neurological decompensation
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 82 (2.44%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    24 / 78 (30.77%)
    23 / 82 (28.05%)
         occurrences all number
    29
    23
    Nausea
         subjects affected / exposed
    9 / 78 (11.54%)
    11 / 82 (13.41%)
         occurrences all number
    9
    11
    Vomiting
         subjects affected / exposed
    5 / 78 (6.41%)
    15 / 82 (18.29%)
         occurrences all number
    5
    15
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 82 (7.32%)
         occurrences all number
    5
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 82 (7.32%)
         occurrences all number
    5
    6
    Pain in extremity
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 82 (4.88%)
         occurrences all number
    4
    4
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 82 (2.44%)
         occurrences all number
    4
    2
    Hypercholesterolaemia
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 82 (3.66%)
         occurrences all number
    6
    3
    Hyperglycaemia
         subjects affected / exposed
    9 / 78 (11.54%)
    3 / 82 (3.66%)
         occurrences all number
    9
    5
    Hypokalaemia
         subjects affected / exposed
    10 / 78 (12.82%)
    10 / 82 (12.20%)
         occurrences all number
    10
    10
    Hyponatraemia
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 82 (6.10%)
         occurrences all number
    3
    5
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    10 / 78 (12.82%)
    6 / 82 (7.32%)
         occurrences all number
    11
    6
    Respiratory tract infection
         subjects affected / exposed
    4 / 78 (5.13%)
    9 / 82 (10.98%)
         occurrences all number
    4
    9
    Urinary tract infection
         subjects affected / exposed
    19 / 78 (24.36%)
    13 / 82 (15.85%)
         occurrences all number
    24
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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