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    Clinical Trial Results:
    Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction

    Summary
    EudraCT number
    		 2017-004854-41
    Trial protocol
    		 GB   DE   CZ   DK   BE   PT   ES   HU   FI   LT   IT   HR  
    Global end of trial date
    18 Aug 2023

    Results information
    Results version number
    		 v1
    This version publication date
    04 Jan 2024
    First version publication date
    04 Jan 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    252LH301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02864953
    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
    18 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 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 improves functional outcomes at Day 90 as measured by the modified Rankin Scale (mRS) when compared with placebo in subjects with Large Hemispheric Infarction (LHI).
    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
    29 Aug 2018
    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
    United States: 228
    Country: Number of subjects enrolled
    Brazil: 46
    Country: Number of subjects enrolled
    China: 45
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Japan: 27
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Worldwide total number of subjects
    535
    EEA total number of subjects
    114
    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)
    300
    From 65 to 84 years
    233
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at investigative sites in the United States, Brazil, China, Spain, Japan, Australia, Portugal, Germany, United Kingdom, Finland, Canada, Israel, France, Taiwan, Hungary, Czech Republic, Italy, Belgium, Lithuania, Russia and South Korea from 29 August 2018 to 18 August 2023.

    Pre-assignment
    Screening details
    		 A total of 535 participants were enrolled and randomised, out of which 518 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
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were administered with BIIB093 matching placebo as an intravenous (IV) bolus on Day 1 followed by a continuous IV infusion for over 72 hours.
    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
    Administered as specified in the treatment arm.

    Arm title
    		 BIIB093
    Arm description
    		 Participants were administered with BIIB093 as an IV bolus on Day 1 followed by continuous IV infusion for over 72 hours.
    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
    Administered as specified in the treatment arm.

    Number of subjects in period 1
    		Placebo BIIB093
    Started
    268
    267
    Completed
    215
    213
    Not completed
    53
    54
         Consent withdrawn by subject
    1
    -
         Physician decision
    4
    2
         Death
    3
    13
         Adverse event
    22
    19
         Reason not specified
    14
    12
         Withdrew Prior to Dosing
    9
    8

    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 on Day 1 followed by a continuous IV infusion for over 72 hours.

    Reporting group title
    BIIB093
    Reporting group description
    		 Participants were administered with BIIB093 as an IV bolus on Day 1 followed by continuous IV infusion for over 72 hours.

    Reporting group values
    		 Placebo BIIB093 Total
    Number of subjects
    		 268 267
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ( 10.81 ) 60.5 ( 11.17 ) -
    Gender categorical
    Units: Subjects
        Male
    		 164 169 333
        Female
    		 104 98 202
    Ethnicity
    Units: Subjects
        Missing
    		 1 2 3
        Hispanic or Latino
    		 36 41 77
        Not Hispanic or Latino
    		 228 223 451
        Not reported
    		 3 1 4
    Race
    Units: Subjects
        Missing
    		 3 2 5
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 53 51 104
        Black or African American
    		 21 19 40
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        White
    		 173 177 350
        Not reported due to confidentiality regulations
    		 3 1 4
        Other
    		 12 16 28

    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 on Day 1 followed by a continuous IV infusion for over 72 hours.

    Reporting group title
    BIIB093
    Reporting group description
    		 Participants were administered with BIIB093 as an IV bolus on Day 1 followed by continuous IV infusion for over 72 hours.

    Primary: Part 1: Percentage of Participants with Improvement in Functional Outcome at Day 90 Assessed via the Modified Rankin Scale (mRS)

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    End point title
    		 Part 1: Percentage of Participants with Improvement in Functional Outcome at Day 90 Assessed via the Modified Rankin Scale (mRS)
    End point description
    The mRS measures the degree of functional independence following stroke. In this study, the 7-category ordinal mRS scale was condensed to the following 5-categories: 0/1, 2, 3, 4, 5/6 where 0 and 1 reflect no disability and near-normal functioning while 5 and 6 represent severe disability and death, respectively. The modified intent to treat (mITT) population included participants aged 18 to 70 years (inclusive) at the time of randomisation, who had received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis.
    End point type
    Primary
    End point timeframe
    Day 90
    End point values
    		 Placebo BIIB093
    Number of subjects analysed
    214
    217
    Units: percentage of participants
    number (not applicable)
        Score: 0/1
    1.4
    3.2
        Score: 2
    2.8
    5.1
        Score: 3
    12.6
    12.0
        Score: 4
    25.2
    23.5
        Score: 5/6
    57.9
    56.2
    Statistical analysis title
    		 Placebo Vs BIIB093
    Comparison groups
    Placebo v BIIB093
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.415 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.71
    Notes
    [1] - P-value was analyzed by ordinal logistic regression adjusting for covariates: region, and IRT stratification factors including rtPA usage (yes/no), thrombectomy usage (yes/no), use of ASPECTS for screening (yes/no), baseline NIHSS (<=20 vs. >20).

    Secondary: Part 1: Time to All-Cause Death Through Day 90

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    End point title
    		 Part 1: Time to All-Cause Death Through Day 90
    End point description
    Time to all-cause death is defined as the time from randomization to the time of death. The mITT population included participants aged 18 to 70 years (inclusive) at the time of randomisation, who received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis. 9999 indicates that median and upper limit of inter quartile range were not reached due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Randomisation up to Day 90
    End point values
    		 Placebo BIIB093
    Number of subjects analysed
    214
    217
    Units: days
        median (inter-quartile range (Q1-Q3))
    9999 (37 to 9999)
    9999 (18 to 9999)
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants Who Achieved mRS 0-4 at Day 90

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    End point title
    		 Part 1: Percentage of Participants Who Achieved mRS 0-4 at Day 90
    End point description
    The mRS measures the degree of functional independence following stroke. In this study, the 7-category ordinal mRS scale was condensed to the following 5-categories: 0/1, 2, 3, 4, 5/6 where 0 and 1 reflect no disability and near-normal functioning while 5 and 6 represent severe disability and death, respectively. The mITT population included participants aged 18 to 70 years (inclusive) at the time of randomisation, who received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. 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
    Number of subjects analysed
    214
    217
    Units: percentage of participants
        number (not applicable)
    41.6
    42.9
    Statistical analysis title
    		 Placebo Vs BIIB093
    Comparison groups
    Placebo v BIIB093
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7413 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.6
    Notes
    [2] - A logistic regression model was used to estimate an odds ratio (and 95% CI) of improvement on the mRS dichotomized as 0-4 vs. 5-6 at Day 90.

    Secondary: Part 1: Reduction in Midline Shift at 72 Hours as Assessed by Non-contrast Computed Tomography (NCCT) or Magnetic Resonance Imaging (MRI)

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    End point title
    		 Part 1: Reduction in Midline Shift at 72 Hours as Assessed by Non-contrast Computed Tomography (NCCT) or Magnetic Resonance Imaging (MRI)
    End point description
    Midline shift is the perpendicular distance between the septum pellucidum and the line drawn between the anterior and posterior attachments of the falx to the inner table of the skull. The mITT population included participants aged 18 to 70 years (inclusive) at the time of randomization, who received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. Here, ‘subjects analysed’ signifies number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    At 72 hours
    End point values
    		 Placebo BIIB093
    Number of subjects analysed
    150
    155
    Units: millimeters (mm)
        arithmetic mean (standard deviation)
    6.32 ( 4.760 )
    7.02 ( 4.565 )
    Statistical analysis title
    		 Placebo Vs BIIB093
    Comparison groups
    Placebo v BIIB093
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1242 [3]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 1.87
    Notes
    [3] - Analysis of Variance (ANOVA) was used to compare the two study arms to assess the treatment effects on midline shift.

    Secondary: Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. The safety population included all participants who were enrolled and had received any portion of the infusion of study treatment (placebo or BIIB093). Here, ‘subjects analysed’ signifies number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    From the signing of informed consent up to last follow-up visit (up to 4 years 11 months)
    End point values
    		 Placebo BIIB093
    Number of subjects analysed
    259
    259
    Units: percentage of participants
    number (not applicable)
        AEs
    95.4
    97.3
        SAEs
    68.3
    76.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the signing of informed consent up to the last follow-up visit (up to 4 years 11 months)
    Adverse event reporting additional description
    The safety population included all participants who were enrolled and had received any portion of the infusion of study treatment (placebo or BIIB093).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    BIIB093
    Reporting group description
    		 Participants were administered with BIIB093 as an IV bolus followed by continuous IV infusion for over 72 hours.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered with BIIB093 matching placebo as an IV bolus followed by a continuous IV infusion for over 72 hours.

    Serious adverse events
    		 BIIB093 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    199 / 259 (76.83%)
    177 / 259 (68.34%)
         number of deaths (all causes)
    104
    97
         number of deaths resulting from adverse events
    104
    97
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cardiac myxoma
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian clear cell carcinoma
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian epithelial cancer metastatic
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Renal cell carcinoma
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    5 / 259 (1.93%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Circulatory collapse
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Arteriosclerosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Shock
         subjects affected / exposed
    1 / 259 (0.39%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Hypotension
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reperfusion injury
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 259 (1.16%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Chest pain
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    3 / 259 (1.16%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    6 / 259 (2.32%)
    6 / 259 (2.32%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    Chronic respiratory failure
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Choking
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Obstructive airways disorder
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory arrest
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory acidosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory depression
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    8 / 259 (3.09%)
    8 / 259 (3.09%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 5
    Respiratory failure
         subjects affected / exposed
    10 / 259 (3.86%)
    11 / 259 (4.25%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 11
         deaths causally related to treatment / all
    0 / 7
    0 / 9
    Respiratory distress
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Delirium tremens
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neurological examination abnormal
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic ulcer haemorrhage
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (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
    19 / 259 (7.34%)
    16 / 259 (6.18%)
         occurrences causally related to treatment / all
    0 / 19
    1 / 17
         deaths causally related to treatment / all
    0 / 15
    0 / 11
    Fall
         subjects affected / exposed
    4 / 259 (1.54%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological procedural complication
         subjects affected / exposed
    11 / 259 (4.25%)
    12 / 259 (4.63%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Post procedural haematoma
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cardiac failure
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Atrial fibrillation
         subjects affected / exposed
    2 / 259 (0.77%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bradycardia
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    5 / 259 (1.93%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Acute myocardial infarction
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Ventricular tachycardia
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Ventricular fibrillation
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dilated cardiomyopathy
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 259 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac ventricular thrombosis
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    10 / 259 (3.86%)
    8 / 259 (3.09%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 8
    0 / 7
    Brain compression
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    72 / 259 (27.80%)
    79 / 259 (30.50%)
         occurrences causally related to treatment / all
    0 / 83
    1 / 85
         deaths causally related to treatment / all
    0 / 35
    0 / 48
    Brain stem haemorrhage
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral mass effect
         subjects affected / exposed
    4 / 259 (1.54%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Lacunar stroke
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 259 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic cerebellar infarction
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic cerebral infarction
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral artery occlusion
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    3 / 259 (1.16%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post stroke epilepsy
         subjects affected / exposed
    4 / 259 (1.54%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    14 / 259 (5.41%)
    16 / 259 (6.18%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 16
         deaths causally related to treatment / all
    0 / 7
    0 / 12
    Hydrocephalus
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intensive care unit acquired weakness
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    8 / 259 (3.09%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Lacunar infarction
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    17 / 259 (6.56%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 5
         deaths causally related to treatment / all
    0 / 14
    0 / 5
    Malignant middle cerebral artery syndrome
         subjects affected / exposed
    2 / 259 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         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
    14 / 259 (5.41%)
    6 / 259 (2.32%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 12
    0 / 5
    Status epilepticus
         subjects affected / exposed
    1 / 259 (0.39%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    6 / 259 (2.32%)
    10 / 259 (3.86%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Subdural hygroma
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 259 (0.77%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Blood loss anaemia
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pelvic floor hernia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 259 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    2 / 259 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute kidney injury
         subjects affected / exposed
    7 / 259 (2.70%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 3
         deaths causally related to treatment / all
    1 / 4
    0 / 2
    Renal tubular necrosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus enteritis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Covid-19
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    3 / 259 (1.16%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterobacter pneumonia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cystitis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 259 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Enterococcal sepsis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    3 / 259 (1.16%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    5 / 259 (1.93%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Gas gangrene
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 259 (5.02%)
    18 / 259 (6.95%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 21
         deaths causally related to treatment / all
    0 / 9
    0 / 8
    Neurosyphilis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella urinary tract infection
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal wall abscess
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematological infection
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    5 / 259 (1.93%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 6
    0 / 7
    Urinary tract infection
         subjects affected / exposed
    6 / 259 (2.32%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    3 / 259 (1.16%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 259 (0.00%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    6 / 259 (2.32%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Sepsis
         subjects affected / exposed
    6 / 259 (2.32%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal abscess
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Proteus infection
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 259 (1.54%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    15 / 259 (5.79%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    19 / 22
    1 / 4
         deaths causally related to treatment / all
    7 / 10
    1 / 3
    Hyponatraemia
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BIIB093 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    201 / 259 (77.61%)
    199 / 259 (76.83%)
    Investigations
    Electrocardiogram qt prolonged
         subjects affected / exposed
    6 / 259 (2.32%)
    13 / 259 (5.02%)
         occurrences all number
    6
    14
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    16 / 259 (6.18%)
    9 / 259 (3.47%)
         occurrences all number
    25
    11
    Hypotension
         subjects affected / exposed
    14 / 259 (5.41%)
    18 / 259 (6.95%)
         occurrences all number
    15
    19
    Hypertension
         subjects affected / exposed
    7 / 259 (2.70%)
    13 / 259 (5.02%)
         occurrences all number
    9
    14
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    13 / 259 (5.02%)
    13 / 259 (5.02%)
         occurrences all number
    13
    13
    Atrial fibrillation
         subjects affected / exposed
    17 / 259 (6.56%)
    22 / 259 (8.49%)
         occurrences all number
    20
    27
    Nervous system disorders
    Haemorrhagic transformation stroke
         subjects affected / exposed
    16 / 259 (6.18%)
    24 / 259 (9.27%)
         occurrences all number
    18
    28
    Headache
         subjects affected / exposed
    22 / 259 (8.49%)
    27 / 259 (10.42%)
         occurrences all number
    30
    31
    Brain oedema
         subjects affected / exposed
    28 / 259 (10.81%)
    28 / 259 (10.81%)
         occurrences all number
    31
    29
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    66 / 259 (25.48%)
    57 / 259 (22.01%)
         occurrences all number
    90
    119
    Pain
         subjects affected / exposed
    14 / 259 (5.41%)
    8 / 259 (3.09%)
         occurrences all number
    18
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    25 / 259 (9.65%)
    28 / 259 (10.81%)
         occurrences all number
    33
    38
    Leukocytosis
         subjects affected / exposed
    16 / 259 (6.18%)
    21 / 259 (8.11%)
         occurrences all number
    17
    23
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 259 (5.02%)
    24 / 259 (9.27%)
         occurrences all number
    16
    29
    Dysphagia
         subjects affected / exposed
    13 / 259 (5.02%)
    6 / 259 (2.32%)
         occurrences all number
    14
    6
    Constipation
         subjects affected / exposed
    40 / 259 (15.44%)
    54 / 259 (20.85%)
         occurrences all number
    45
    64
    Vomiting
         subjects affected / exposed
    22 / 259 (8.49%)
    26 / 259 (10.04%)
         occurrences all number
    23
    32
    Nausea
         subjects affected / exposed
    13 / 259 (5.02%)
    17 / 259 (6.56%)
         occurrences all number
    13
    18
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    10 / 259 (3.86%)
    20 / 259 (7.72%)
         occurrences all number
    10
    23
    Acute kidney injury
         subjects affected / exposed
    17 / 259 (6.56%)
    11 / 259 (4.25%)
         occurrences all number
    19
    11
    Infections and infestations
    Pneumonia aspiration
         subjects affected / exposed
    15 / 259 (5.79%)
    14 / 259 (5.41%)
         occurrences all number
    16
    15
    Pneumonia
         subjects affected / exposed
    32 / 259 (12.36%)
    40 / 259 (15.44%)
         occurrences all number
    32
    44
    Urinary tract infection
         subjects affected / exposed
    29 / 259 (11.20%)
    41 / 259 (15.83%)
         occurrences all number
    31
    52
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    26 / 259 (10.04%)
    23 / 259 (8.88%)
         occurrences all number
    33
    24
    Hyperglycaemia
         subjects affected / exposed
    14 / 259 (5.41%)
    15 / 259 (5.79%)
         occurrences all number
    18
    41
    Hypocalcaemia
         subjects affected / exposed
    13 / 259 (5.02%)
    11 / 259 (4.25%)
         occurrences all number
    14
    11
    Hypoglycaemia
         subjects affected / exposed
    31 / 259 (11.97%)
    8 / 259 (3.09%)
         occurrences all number
    54
    18
    Hypokalaemia
         subjects affected / exposed
    35 / 259 (13.51%)
    32 / 259 (12.36%)
         occurrences all number
    44
    36
    Hyponatraemia
         subjects affected / exposed
    18 / 259 (6.95%)
    18 / 259 (6.95%)
         occurrences all number
    20
    21
    Hypophosphataemia
         subjects affected / exposed
    14 / 259 (5.41%)
    23 / 259 (8.88%)
         occurrences all number
    15
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2020
    Increased the permitted percentage of subjects with endovascular thrombectomy performed prior to randomisation. The total daily dose was revised. The planned size of the primary efficacy population (≤70 years of age) was adjusted. Inclusion criterion 8 was revised to define time to randomization in relation to time of last known normal or symptom onset. Text was revised to remove laboratory tests that are not considered essential to laboratory safety assessments. Conditions under which study treatment must be permanently discontinued were revised to include management of study treatment in the presence of hypoglycemia. Withdrawal of subjects from the study was updated to specify that subjects who withdraw from the study may not be replaced. The Synopsis was revised to note the increase in the number of study sites. The text stating that BIIB093 is being studied for brain contusion as well as large hemispheric infarction was added. The Schedule of Activities was revised to include ‘The Day 90 visit should be conducted in person whenever possible followed by telemedicine or phone in order of preference. All other visits after hospital discharge can be conducted by telephone/telemedicine or in person at the study subject’s/representative’s request’. Text regarding early termination was added; ‘Early termination is defined as withdrawal from the study. Subjects who discontinue study treatment for any reason or who move to comfort care/palliative care should not be withdrawn from the study (see Section 10.1). Rather, they should either continue protocol-required tests and assessments or continue in the study with a limited study assessment schedule’. Text stating Pre-morbid mRS will be collected based on all available information including medical records, patient, family, and/or LAR reports was added as a footnote. Text was revised to allow more flexibility for PK and matrix metalloproteinase-9 (MMP-9) sampling around the time of the bolus infusion.
    11 Jun 2021
    Text regarding interim analysis was updated - An interim futility analysis may be performed based on the primary endpoint when approximately 30% of planned mITT participants complete Day 90

    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 operational challenges and other strategic considerations, not for efficacy or safety reasons.
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