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    Clinical Trial Results:
    A Multicenter, Double-Blind, Multidose, Placebo-Controlled, Randomized, Parallel-Group, Phase 2 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 for Patients With Brain Contusion

    Summary
    EudraCT number
    		 2018-003858-24
    Trial protocol
    		 ES   IT  
    Global end of trial date
    27 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2023
    First version publication date
    15 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    252BN201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03954041
    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
    27 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine if BIIB093 reduces brain contusion expansion by Hour 96 when compared to placebo. The secondary objectives were to evaluate the effects of BIIB093 on acute neurologic status, functional outcomes, and treatment requirements, to further differentiate the mechanism of action of BIIB093 on contusion expansion by examining differential effects on hematoma and edema expansion, and to determine if BIIB093 improves survival at Day 90 when compared to placebo.
    Protection of trial subjects
    Written informed consent was obtained from each participant or participant’s legally authorized representative (e.g., legal guardian), as applicable, prior to evaluations performed for eligibility. Participants or the participant’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Israel: 2
    Worldwide total number of subjects
    86
    EEA total number of subjects
    51
    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)
    54
    From 65 to 84 years
    31
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study centers in Israel, France, Japan, Italy, Spain, and the United States.

    Pre-assignment
    Screening details
    		 A total of 92 participants were enrolled and randomized, out of which 86 participants were dosed with BIIB093 or a matching placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were administered with BIIB093 matching placebo as an intravenous (IV) bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIIB093 matching placebo administered as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Arm title
    		 BIIB093 3 mg/day
    Arm description
    		 Participants were administered with BIIB093 up to 3 milligrams per day (mg/day) as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB093
    Investigational medicinal product code
    Other name
    Glibenclamide, CIRARA, RP 1127
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Up to 3mg/day BIIB093 administered as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Arm title
    		 BIIB093 5 mg/day
    Arm description
    		 Participants were administered with BIIB093 up to 5 mg/day as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB093
    Investigational medicinal product code
    Other name
    Glibenclamide, CIRARA, RP 1127
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Up to 5mg/day BIIB093 administered as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Number of subjects in period 1
    		Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Started
    44
    21
    21
    Completed
    30
    14
    11
    Not completed
    14
    7
    10
         Adverse event, serious fatal
    4
    -
    1
         Other
    7
    4
    2
         Lost to follow-up
    3
    3
    6
         Death by neurologic criteria
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered with BIIB093 matching placebo as an intravenous (IV) bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group title
    BIIB093 3 mg/day
    Reporting group description
    		 Participants were administered with BIIB093 up to 3 milligrams per day (mg/day) as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group title
    BIIB093 5 mg/day
    Reporting group description
    		 Participants were administered with BIIB093 up to 5 mg/day as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day Total
    Number of subjects
    		 44 21 21
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.3 ± 14.18 55.7 ± 19.87 55.0 ± 21.02 -
    Gender categorical
    Units: Subjects
        Male
    		 36 18 18 72
        Female
    		 8 3 3 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 4 8
        Not Hispanic or Latino
    		 39 15 14 68
        Not Reported
    		 3 4 3 10
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 1
        Asian
    		 12 5 5 22
        Black or African American
    		 1 0 0 1
        White
    		 26 12 13 51
        Not Reported
    		 2 4 3 9
        Other
    		 2 0 0 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered with BIIB093 matching placebo as an intravenous (IV) bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group title
    BIIB093 3 mg/day
    Reporting group description
    		 Participants were administered with BIIB093 up to 3 milligrams per day (mg/day) as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group title
    BIIB093 5 mg/day
    Reporting group description
    		 Participants were administered with BIIB093 up to 5 mg/day as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Primary: Change From Baseline in Mean Total Contusion Volume (Hematoma Plus Perihematomal Edema) at 96 Hours as Measured by Brain Imaging

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    End point title
    		 Change From Baseline in Mean Total Contusion Volume (Hematoma Plus Perihematomal Edema) at 96 Hours as Measured by Brain Imaging
    End point description
    Total contusion volume including hematoma and perihematomal edema volumes reported in mL was assessed by the central imaging core laboratory on baseline non-contrast computed tomography (NCCT), 24-hour NCCT, and the 96-hour scan (Magnetic resonance imaging [MRI and/or NCCT) and the scans obtained prior to decompressive craniectomy (DC), intraparenchymal hematoma (IPH) evacuation, or comfort measures only (CMO). Modified intent to treat (mITT) population included all randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after initiation of study drug infusion and Hour 96 visit or neurosurgical intervention (NSx) or CMO, if earlier. Here, ‘subjects analysed’ signifies number of participants with data available for endpoint analysis. ‘Number analysed (n)' signifies number of participants with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline up to 96 hours (Day 4)
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    38
    20
    19
    Units: milliliters (mL)
    arithmetic mean (standard deviation)
        Baseline (n=38,20, 19)
    29.45 ± 29.688
    21.21 ± 26.659
    21.33 ± 26.637
        Change From Baseline at 96 hours (n=34,19,15)
    18.91 ± 23.804
    30.07 ± 29.418
    18.78 ± 12.771
    Statistical analysis title
    		 Combined BIIB093 vs Placebo
    Comparison groups
    Placebo v BIIB093 3 mg/day v BIIB093 5 mg/day
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3752 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    4.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.74
         upper limit
    		 14.98
    Notes
    [1] - P-value was analyzed by ANCOVA model with covariates: treatment, interactive response technology (IRT) stratification factors at randomization, baseline total contusion volume based on central read, imaging modality at Hour 96 (MRI vs NCCT).

    Secondary: Percentage of Participants With Glasgow Outcome Scale - Extended (GOS-E) Score at Day 180

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    End point title
    		 Percentage of Participants With Glasgow Outcome Scale - Extended (GOS-E) Score at Day 180
    End point description
    The GOS-E is a global scale for functional outcomes that rates participant status on a 7-category ordinal scale into one of five categories: 1 and 2: Dead and Vegetative State, 3 and 4: Severe disability lower and upper categories, 5 and 6: Moderate disability lower and upper categories, 7 and 8: Good recovery lower and upper categories. Lower scores indicate death and higher scores indicate recovery. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Day 180
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    30
    15
    11
    Units: percentage of participants
    number (not applicable)
        Score: 1/2
    0
    0
    0
        Score: 3
    13.3
    13.3
    27.3
        Score: 4
    0
    26.7
    9.1
        Score: 5
    13.3
    6.7
    0
        Score: 6
    26.7
    0
    0
        Score: 7
    6.7
    13.3
    27.3
        Score: 8
    40.0
    40.0
    36.4
    Statistical analysis title
    		 Combined BIIB093 vs Placebo
    Comparison groups
    Placebo v BIIB093 3 mg/day v BIIB093 5 mg/day
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 3.36

    Secondary: Percentage of Participants With Modified Rankin Scale (mRS) Score at Day 90

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    End point title
    		 Percentage of Participants With Modified Rankin Scale (mRS) Score at Day 90
    End point description
    The mRS measures the degree of disability or dependence in the daily activities of participants who had suffered a stroke or other causes of neurological disability on a 5-category ordinal scale: 0/1, 2, 3, 4, 5/6. Lower scores indicate perfect health without symptoms and higher scores indicate death. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    39
    19
    14
    Units: percentage of participants
    number (not applicable)
        Score: 0/1
    38.5
    31.6
    57.1
        Score: 2
    25.6
    26.3
    7.1
        Score: 3
    12.8
    21.1
    0
        Score: 4
    10.3
    15.8
    21.4
        Score: 5/6
    12.8
    5.3
    14.3
    Statistical analysis title
    		 Combined BIIB093 vs Placebo
    Comparison groups
    Placebo v BIIB093 3 mg/day v BIIB093 5 mg/day
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4306 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 3.86
    Notes
    [2] - P-value was analysed by ordinal logistic regression on mRS adjusting for covariates: treatment, IRT stratification factors at randomisation, baseline GCS based on eCRF, baseline mRS score, and baseline total contusion volume based on central read.

    Secondary: Percentage of Participants Requiring Delayed Intubation

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    End point title
    		 Percentage of Participants Requiring Delayed Intubation
    End point description
    Delayed intubation is defined as participants requiring intubation (for neurologic deterioration only) at any time between 24 hours and 96 hours post-injury. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier.
    End point type
    Secondary
    End point timeframe
    Day 1 (24 hours) up to Day 4 (96 hours) post-injury
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    44
    21
    20
    Units: percentage of participants
        number (not applicable)
    2.3
    4.8
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Total Contusion Volume (Hematoma Plus Perihematomal Edema) to 24 Hours as Measured by Brain Imaging

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    End point title
    		 Change From Baseline in Mean Total Contusion Volume (Hematoma Plus Perihematomal Edema) to 24 Hours as Measured by Brain Imaging
    End point description
    Total contusion volume including hematoma and perihematomal edema volumes reported in mL was assessed by the central imaging core laboratory on baseline NCCT, 24-hour NCCT. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis. ‘Number analysed (n)' signifies the number of participants with data available for analysis at a specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 hours (Day 1)
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    38
    20
    19
    Units: mL
    arithmetic mean (standard deviation)
        Baseline (n=38, 20, 19)
    29.45 ± 29.688
    21.21 ± 26.659
    21.33 ± 26.637
        Change From Baseline at 24 hours (n= 36, 19, 18)
    8.16 ± 18.824
    11.24 ± 13.909
    6.67 ± 13.483
    Statistical analysis title
    		 Combined BIIB093 vs Placebo
    Comparison groups
    Placebo v BIIB093 3 mg/day v BIIB093 5 mg/day
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6478 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.19
         upper limit
    		 5.13
    Notes
    [3] - P-value was analyzed by ANCOVA model with covariates: treatment, IRT stratification factors at randomization, baseline total contusion volume based on central read.

    Secondary: Change From Baseline in Absolute Hematoma Volume at 24 Hours

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    End point title
    		 Change From Baseline in Absolute Hematoma Volume at 24 Hours
    End point description
    Hematoma volume reported in mL was assessed by the central imaging core laboratory on baseline NCCT, 24-hour NCCT, and the scans obtained prior to DC, IPH evacuation, or CMO. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis. 'Number analysed (n)' signifies the number of participants with data available for analysis at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 hours (Day 1)
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    40
    20
    20
    Units: mL
    arithmetic mean (standard deviation)
        Baseline (n=40, 20, 20)
    6.72 ± 10.012
    6.11 ± 12.086
    3.62 ± 3.737
        Change From Baseline at 24 hours (n=38, 19, 19)
    2.07 ± 5.920
    2.13 ± 3.667
    2.23 ± 3.537
    Statistical analysis title
    		 Combined BIIB093 vs Placebo
    Comparison groups
    Placebo v BIIB093 3 mg/day v BIIB093 5 mg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9314 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 2.02
    Notes
    [4] - P-value was analyzed by ANCOVA model with covariates: treatment, IRT stratification factors at randomization, baseline Glasgow Coma Scale (GCS) based on eCRF, and baseline absolute hematoma volume based on central read.

    Secondary: Change From Baseline in Absolute Edema Volume at 96 Hours

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    End point title
    		 Change From Baseline in Absolute Edema Volume at 96 Hours
    End point description
    Edema volume reported in mL was assessed by the central imaging core laboratory on baseline NCCT, 24-hour NCCT, and the 96-hour scan (MRI and/or NCCT) and the scans obtained prior to DC, IPH evacuation, or CMO. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis. ‘Number analysed (n)' signifies the number of participants with data available for analysis at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 96 hours (Day 4)
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    38
    20
    19
    Units: mL
    arithmetic mean (standard deviation)
        Baseline (n=38, 20, 19)
    22.41 ± 23.234
    15.10 ± 16.366
    17.52 ± 24.103
        Change From Baseline at 96 hours (n=34, 19, 15)
    16.13 ± 20.872
    25.87 ± 27.772
    14.98 ± 10.459
    Statistical analysis title
    		 Combined BIIB093 vs Placebo
    Comparison groups
    Placebo v BIIB093 3 mg/day v BIIB093 5 mg/day
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6569 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.61
         upper limit
    		 11.98
    Notes
    [5] - P-value was analyzed by ANCOVA model with covariates: treatment, IRT stratification factors at randomization, baseline absolute edema volume based on central read, baseline GCS based on eCRF, and imaging modality at Hour 96 (MRI vs NCCT).

    Secondary: Time to All-Cause Death Through Day 90

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    End point title
    		 Time to All-Cause Death Through Day 90
    End point description
    Time to all-cause death is defined as the time from randomisation to the time of death and includes all-cause death along with neurological death. mITT population included all the randomised participants who received any study drug (BIIB093 or placebo) and had at least one final read per central review of contusion volume from a NCCT or MRI scan acquired between 10 hours after the initiation of study drug infusion and the Hour 96 visit or NSx or CMO, if earlier. Here, ‘subjects analysed’ signifies the number of participants who died from randomisation up to Day 90. 9999=Not estimable due to the small number of deaths.
    End point type
    Secondary
    End point timeframe
    Randomisation up to Day 90
    End point values
    		 Placebo BIIB093 3 mg/day BIIB093 5 mg/day
    Number of subjects analysed
    3
    0 [6]
    1
    Units: days
        median (inter-quartile range (Q1-Q3))
    9999 (9999 to 9999)
    ( to )
    9999 (9999 to 9999)
    Notes
    [6] - Zero deaths were observed in this arm group.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent up to last follow-up visit (approximately 1360 days)
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who had received any infusion of the study drug (BIIB093 or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered with BIIB093 matching placebo as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group title
    BIIB093 5mg/day
    Reporting group description
    		 Participants were administered with BIIB093 up to 5 mg/day as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Reporting group title
    BIIB093 3mg/day
    Reporting group description
    		 Participants were administered with BIIB093 up to 3 mg/day as an IV bolus followed by a rapid IV infusion and a slow IV infusion for 4 days.

    Serious adverse events
    		 Placebo BIIB093 5mg/day BIIB093 3mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 44 (27.27%)
    8 / 19 (42.11%)
    7 / 23 (30.43%)
         number of deaths (all causes)
    4
    2
    0
         number of deaths resulting from adverse events
    4
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Clavicle fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Subdural haematoma
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         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
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Cardiac arrest
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Epilepsy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 19 (15.79%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (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
    Rectal haemorrhage
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Apnoea
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Korsakoff's syndrome
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Infections and infestations
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Klebsiella sepsis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Pneumonia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (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
    Urosepsis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 19 (21.05%)
    4 / 23 (17.39%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BIIB093 5mg/day BIIB093 3mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 44 (81.82%)
    18 / 19 (94.74%)
    20 / 23 (86.96%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 44 (13.64%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    8
    0
    1
    Hypertension
         subjects affected / exposed
    9 / 44 (20.45%)
    4 / 19 (21.05%)
    6 / 23 (26.09%)
         occurrences all number
    9
    4
    6
    Phlebitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Hypothermia
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 19 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    4
    0
    0
    Generalised oedema
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Asthenia
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    2
    0
    2
    Medical device site erosion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    9 / 44 (20.45%)
    3 / 19 (15.79%)
    6 / 23 (26.09%)
         occurrences all number
    10
    3
    6
    Oedema peripheral
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 19 (5.26%)
    2 / 23 (8.70%)
         occurrences all number
    3
    2
    2
    Reproductive system and breast disorders
    Priapism
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory alkalosis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory acidosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    3
    0
    1
    Atelectasis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    3 / 23 (13.04%)
         occurrences all number
    3
    0
    3
    Disorientation
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    0
    Delirium
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 19 (15.79%)
    1 / 23 (4.35%)
         occurrences all number
    1
    3
    1
    Confusional state
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    1
    Agitation
         subjects affected / exposed
    6 / 44 (13.64%)
    3 / 19 (15.79%)
    1 / 23 (4.35%)
         occurrences all number
    6
    3
    1
    Irritability
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    6 / 44 (13.64%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    6
    0
    2
    Electroencephalogram abnormal
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    3
    0
    1
    Fibrin d dimer increased
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    4
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    2
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 44 (11.36%)
    0 / 19 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    5
    0
    0
    Injury, poisoning and procedural complications
    Brain contusion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Bradycardia
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 19 (10.53%)
    4 / 23 (17.39%)
         occurrences all number
    5
    2
    4
    Atrial fibrillation
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 19 (5.26%)
    2 / 23 (8.70%)
         occurrences all number
    3
    1
    2
    Tachycardia
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 19 (5.26%)
    2 / 23 (8.70%)
         occurrences all number
    3
    1
    2
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Anosmia
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    3
    0
    2
    Aphasia
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    7
    0
    4
    Cognitive disorder
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    1
    0
    2
    Dementia with lewy bodies
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 19 (10.53%)
    1 / 23 (4.35%)
         occurrences all number
    3
    2
    1
    Epilepsy
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 19 (5.26%)
    2 / 23 (8.70%)
         occurrences all number
    3
    1
    2
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Syncope
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Subdural hygroma
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    1
    0
    2
    Seizure
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Neurological decompensation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    3
    0
    1
    Lateral medullary syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Lacunar infarction
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Intracranial pressure increased
         subjects affected / exposed
    5 / 44 (11.36%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    5
    1
    0
    Headache
         subjects affected / exposed
    7 / 44 (15.91%)
    2 / 19 (10.53%)
    4 / 23 (17.39%)
         occurrences all number
    7
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 19 (10.53%)
    2 / 23 (8.70%)
         occurrences all number
    5
    2
    2
    Dilutional anaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    1
    0
    2
    Eye disorders
    Anisocoria
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 19 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    6
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 19 (5.26%)
    5 / 23 (21.74%)
         occurrences all number
    4
    1
    5
    Salivary hypersecretion
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    4
    0
    1
    Proctitis haemorrhagic
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 19 (15.79%)
    1 / 23 (4.35%)
         occurrences all number
    3
    3
    1
    Dysphagia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Diarrhoea
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 19 (5.26%)
    3 / 23 (13.04%)
         occurrences all number
    3
    1
    3
    Constipation
         subjects affected / exposed
    10 / 44 (22.73%)
    2 / 19 (10.53%)
    6 / 23 (26.09%)
         occurrences all number
    11
    2
    6
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Cholestasis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 19 (0.00%)
    3 / 23 (13.04%)
         occurrences all number
    1
    0
    3
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    0
    3
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    5 / 44 (11.36%)
    0 / 19 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    5
    0
    1
    Oliguria
         subjects affected / exposed
    5 / 44 (11.36%)
    1 / 19 (5.26%)
    3 / 23 (13.04%)
         occurrences all number
    5
    1
    3
    Dysuria
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 19 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    Acute kidney injury
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 19 (5.26%)
    2 / 23 (8.70%)
         occurrences all number
    3
    1
    2
    Back pain
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    2 / 23 (8.70%)
         occurrences all number
    2
    1
    3
    Plantar fasciitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Escherichia infection
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Pneumonia
         subjects affected / exposed
    9 / 44 (20.45%)
    3 / 19 (15.79%)
    3 / 23 (13.04%)
         occurrences all number
    9
    3
    3
    Pneumonia aspiration
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    1
    Tracheobronchitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Covid-19
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    2
    1
    0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 19 (10.53%)
    1 / 23 (4.35%)
         occurrences all number
    1
    2
    1
    Hyperchloraemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 19 (5.26%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 19 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    4
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 19 (15.79%)
    7 / 23 (30.43%)
         occurrences all number
    1
    3
    9
    Hypokalaemia
         subjects affected / exposed
    10 / 44 (22.73%)
    2 / 19 (10.53%)
    6 / 23 (26.09%)
         occurrences all number
    11
    2
    6
    Hyponatraemia
         subjects affected / exposed
    6 / 44 (13.64%)
    1 / 19 (5.26%)
    6 / 23 (26.09%)
         occurrences all number
    6
    1
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2020
    • The age range for study inclusion was increased from up to 80 years old to up to 85 years old. In addition, the Glasgow Coma Scale (GCS) score range for study inclusion was increased from up to 14 to up to 15 • Updated text to clarify definition of low blood glucose (BG) • Updated text to clarify if a participant is discharged from the hospital prior to Hour 96, sites should still obtain neuroimaging prior to the participant departing the hospital • Updated text to clarify that participants can get a NCCT scan if an MRI is not possible and that Hour 96 MRI scan should be performed within 18 hours of the Hour 96 time point • Pharmacokinetic (PK) objectives related to evaluation of BIIB093 was updated • Added text to clarify the mechanism of injury for study inclusion; exclusion criteria for NCCT or MRI; use of transient vasopressor, interventional radiology procedures for embolization, vitamin K antagonists • Suicidal ideation assessment was added to the schedule of activities at baseline and follow-up • Updated text to clarify blinding procedure, storage requirement of BIIB093, laboratory yests for safety assessments • Qualified neurosurgical interventions (NSx) including decompressive craniectomy (DC) and requirement for imaging studies were clarified • The images used to determine the primary endpoint and the timing of scans for contusion volume were clarified; timing for analysis requiring delayed intubation was clarified.
    13 Nov 2022
    • The study population was expanded to include participants indicated for surgery and those with survivable polytrauma facilitated by the removal of midline shift and injury severity score thresholds. The dosing time window was extended to 10 hours to allow for additional participants to be treated including inter-hospital transfers. An interim analysis was conducted by a separate unblinded team that facilitated an early start to Phase 3 planning while continuing the Phase 2 as a blinded study • Clarified that exposure data from the 5 mg/day dose was the result of simulations • Added text pertaining to scans in relation to IPH evacuation, DC, or CMO was added to the NCCT and MRI, optional NCCT scans • Updated assessment language regarding MRI/NCCT • Primary endpoint was amended to increase statistical power to detect a meaningful treatment effect while recognizing any reduction in contusion volume is desirable to detect • The GOS-E at Day 180 was removed as an additional endpoint and added as one of the secondary endpoints. GOS-E at Day 90 was removed as a secondary endpoint and added as one of the additional endpoints • Change in total contusion volume (hematoma plus perihematomal edema) from baseline to 24 hours was added as one of the secondary endpoints • The additional endpoint stating the proportion of participants requiring NSx, including craniotomy and DC, was removed • The new endpoint of proportion of participants requiring DC or IPH evacuation between 24 and 96 hours after trauma was added.

    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.
    Early termination of trial due to strategic considerations, not for efficacy or safety reasons.
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