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    Clinical Trial Results:
    Clot lysis: evaluating accelerated resolution of intraventricular hemorrhage Phase III

    Summary
    EudraCT number
    		 2008-006916-39
    Trial protocol
    		 GB   ES   DE  
    Global end of trial date
    13 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Oct 2019
    First version publication date
    17 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IVH06
    Additional study identifiers
    ISRCTN number
    		 ISRCTN70157009
    US NCT number
    		 NCT00784134
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 8523
    Sponsors
    Sponsor organisation name
    Newcastle University, Neurosurgical Trials Unit
    Sponsor organisation address
    3-4 Claremont Terrace, Newcastle upon Tyne, United Kingdom, NE2 4AE
    Public contact
    Dr Barbara A Gregson, Newcastle University, 44 0191 222 5793, barbara.gregson@ncl.ac.uk
    Scientific contact
    Dr Barbara A Gregson, Newcastle University, 44 0191 222 5793, barbara.gregson@ncl.ac.uk
    Sponsor organisation name
    Johns Hopkins University
    Sponsor organisation address
    750 East Pratt Street, 16th Floor, Baltimore, United States, 21202
    Public contact
    Daniel F. Hanley, MD, Johns Hopkins University, +1 410-361-7999, dhanley2@jh.edu
    Scientific contact
    Karen Lane, Johns Hopkins University, +1 410-361-7999, klane@jhmi.edu
    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
    15 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To define precisely the long-term effects of lysing ventricular blood clots with rt-PA on the functional outcomes of cerebral hemorrhage patients. We propose to test if this intervention promotes a recovery of function, as defined as a modified Rankin score of < 3 at 180 days post ictus, by facilitating more rapid clot resolution as compared to treatment with extraventricular drainage (EVD) with placebo.
    Protection of trial subjects
    1. Adherence to inclusion and exclusion criteria during screening 2. Explaining potential risks to participants during informed consent 3. Ethical / Institutional Review Board and DSMB team to evaluate safety of the study drug 4. Subject confidentiality 5. Human Subjects Research Training completed for all study staff. 6. Women who become pregnant during the follow-up period will be followed through 12 month visit to document clinical and functional outcome but no CT scans will be done. 7. All subjects stabilized for at least 6 hours prior to the first dose of test article. 8. All adverse events monitored throughout the initial hospitalization and during the 12 month follow-up period 9. All infections will be reported to the safety and monitoring committee for an independent assessment of clinical significance
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    United States: 370
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Israel: 37
    Country: Number of subjects enrolled
    Switzerland: 4
    Worldwide total number of subjects
    500
    EEA total number of subjects
    76
    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)
    354
    From 65 to 84 years
    146
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants aged 18–80 years with known symptom onset within 24 h of the initial CT scan confirming intraventricular haemorrhage and 3rd or 4th ventricle obstruction were recruited to participate in the study.

    Pre-assignment
    Screening details
    		 Eligibility criteria included supratentorial intracerebral haemorrhage volume 30 mL or less, measured by the ABC/2 method,18,19 and clot stability (no measured expansion >5 mL) on repeat CT scan at least 6 h after extraventricular drain placement

    Period 1
    Period 1 title
    Overall trial (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
    		 Alteplase
    Arm description
    		 Administration of alteplase via the intraventricular catheter 1.0 mg of alteplase will be administered via the intraventricular catheter every 8 hours for up to 12 doses Other Names: Cathflo Activase, rt-PA
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alteplase
    Investigational medicinal product code
    Other name
    rtPA, Cathflo Activase
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intraventricular use
    Dosage and administration details
    1.0 mg of alteplase will be administered via the intraventricular catheter every 8 hours for up to 12 doses

    Arm title
    		 Saline Placebo
    Arm description
    		 1 ml of normal saline administered via the intraventricular catheter Normal saline: 1 ml of normal saline will be administered via the intraventricular catheter every 8 hours for up to 12 doses
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intraventricular use
    Dosage and administration details
    1 ml of normal saline administered via the intraventricular catheter

    Number of subjects in period 1
    		Alteplase Saline Placebo
    Started
    249
    251
    Completed
    246
    245
    Not completed
    3
    6
         Lost to follow-up
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alteplase
    Reporting group description
    		 Administration of alteplase via the intraventricular catheter 1.0 mg of alteplase will be administered via the intraventricular catheter every 8 hours for up to 12 doses Other Names: Cathflo Activase, rt-PA

    Reporting group title
    Saline Placebo
    Reporting group description
    		 1 ml of normal saline administered via the intraventricular catheter Normal saline: 1 ml of normal saline will be administered via the intraventricular catheter every 8 hours for up to 12 doses

    Reporting group values
    		 Alteplase Saline Placebo Total
    Number of subjects
    		 249 251 500
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 182 172 354
        From 65-84 years
    		 67 79 146
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 59 (51 to 66) 59 (51 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 105 117 222
        Male
    		 144 134 278
    Race
    Units: Subjects
        American Indian or Alaskan Native
    		 0 1 1
        Asian
    		 7 7 14
        Native Hawaiian or Other Pacific Islander
    		 3 1 4
        Black or African American
    		 92 78 170
        White
    		 144 161 305
        More than one race
    		 0 1 1
        Unknown or Not reported
    		 3 2 5
    Region of enrollment
    Units: Subjects
        Canada
    		 3 6 9
        Hungary
    		 7 6 13
        United States
    		 190 180 370
        Brazil
    		 1 3 4
        United Kingdom
    		 4 4 8
        Israel
    		 13 24 37
        Switzerland
    		 1 3 4
        Germany
    		 21 18 39
        Spain
    		 9 7 16

    End points

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    End points reporting groups
    Reporting group title
    Alteplase
    Reporting group description
    		 Administration of alteplase via the intraventricular catheter 1.0 mg of alteplase will be administered via the intraventricular catheter every 8 hours for up to 12 doses Other Names: Cathflo Activase, rt-PA

    Reporting group title
    Saline Placebo
    Reporting group description
    		 1 ml of normal saline administered via the intraventricular catheter Normal saline: 1 ml of normal saline will be administered via the intraventricular catheter every 8 hours for up to 12 doses

    Primary: 1. Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis

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    End point title
    		 1. Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis
    End point description
    Analysis modified on September 29, 2015 to account for adaptive randomization. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. The dichotomized scores are as follows: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death. All the non-missing mRS scores at 180 days were analyzed. Number and proportions reported refer to number of participants with Modified Rankin Score 0-3
    End point type
    Primary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    246 [1]
    245 [2]
    Units: Number of participants
    117
    110
    Notes
    [1] - All patients with non-missing data at 180 days were analysed
    [2] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.554
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.062
         upper limit
    		 0.115
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Multivariable logit model adjusted for age, GCS, thalamus, stability ICH volume and stability IVH volume.
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.465
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.87

    Primary: 2. Participant Score on the Modified Rankin Scale (mRS) - Ordinal Analysis

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    End point title
    		 2. Participant Score on the Modified Rankin Scale (mRS) - Ordinal Analysis
    End point description
    End point type
    Primary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    246 [3]
    245 [4]
    Units: Unit of measure
        median (inter-quartile range (Q1-Q3))
    4 (3 to 5)
    4 (3 to 6)
    Notes
    [3] - All patients with non-missing data at 180 days were analysed
    [4] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.484
    Method
    		 Generalized ordered Logit model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.25
    Notes
    [5] - Generalized ordered logit model adjusted for age, GCS, thalamus, stability ICH volume and stability IVH volume (categorical) compares odds ratio for mRS score > K v. <= K for K = 1 - 4; Alt v. Sal.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 Generalized ordered Logit model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.71
    Notes
    [6] - The same generalized ordered logit model, adjusting for age, GCS, thalamus, stability ICH volume and stability IVH volume (categorical), compares odds ratio for mRS score greater than 5 versus mRS score equal or less than 5 (dead versus alive).

    Primary: 3. Participants With Modified Rankin Scale (mRS) <=4 - Dichotomized Analysis

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    End point title
    		 3. Participants With Modified Rankin Scale (mRS) <=4 - Dichotomized Analysis
    End point description
    The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-4=No symptoms to moderately severe disability requiring some assistance; 5-6=Severe disability requiring complete assistance to death.
    End point type
    Primary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    246 [7]
    245 [8]
    Units: Number of participants
    158
    151
    Notes
    [7] - All patients with non-missing data at 180 days were analysed
    [8] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.552
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.059
         upper limit
    		 0.111
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35 [9]
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.9
    Notes
    [9] - Multivariable logit model adjusting for age, GCS, thalamus, stability ICH volume and stability IVH volume (categorical).

    Primary: 4. Random Effects Assessment of Site Effect on Modified Rankin Scale (mRS) <= 3

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    End point title
    		 4. Random Effects Assessment of Site Effect on Modified Rankin Scale (mRS) <= 3
    End point description
    Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 180 days post-ictus. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death
    End point type
    Primary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    246 [10]
    245 [11]
    Units: Number of participants
    117
    110
    Notes
    [10] - All patients with non-missing data at 180 days were analysed
    [11] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.428 [12]
    Method
    		 Random Effects Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.8
    Notes
    [12] - Random effects model with site as random effect adjusted for age GCS, thalamus, stability ICH volume and stability IVH volume (categorical).

    Primary: 5.Longitudinal Assessment of Participants With Modified Rankin Scale (mRS) <=3

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    End point title
    		 5.Longitudinal Assessment of Participants With Modified Rankin Scale (mRS) <=3
    End point description
    Comparing longitudinal modified Rankin Scale (mRS) scores 0-3 at Day 30 and Day 180. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death.
    End point type
    Primary
    End point timeframe
    30 days and 180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    246 [13]
    245 [14]
    Units: Number of participants
        Day 30
    50
    41
        Day 180
    110
    117
    Notes
    [13] - All patients with non-missing data at 30 days and 180 days were analysed
    [14] - All patients with non-missing data at 30 days and 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Logit mRS scores 0-3 at 30 days
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.384 [15]
    Method
    		 Generalized Estimating Equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 2.1
    Notes
    [15] - Generalized estimating equation model adjusting for age, GCS, thalamus, stability ICH volume and stability IVH volume (categorical)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Logit mRS scores 0-3 at 180 days
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.964 [16]
    Method
    		 Generalized Estimating Equation model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.64
    Notes
    [16] - Generalized estimating equation model adjusting for age, GCS, thalamus, stability ICH volume and stability IVH volume (categorical).

    Secondary: 6. All Cause Mortality

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    End point title
    		 6. All Cause Mortality
    End point description
    All cause mortality among all patients that were enrolled in CLEAR III were analyzed
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Numberof participants
    46
    73
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056
    Method
    		 Logrank
    Confidence interval

    Secondary: 7. Clot Removal (Amount of Residual Blood)

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    End point title
    		 7. Clot Removal (Amount of Residual Blood)
    End point description
    Change in blood volume measured between stability scan and end of treatment scan
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: odds ratio per time -weighted mL
        number (not applicable)
    0.96
    0.97
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 AUC/Logit Model
    Confidence interval

    Secondary: 8. Intensity of Critical Care Management - Hospital Days

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    End point title
    		 8. Intensity of Critical Care Management - Hospital Days
    End point description
    Intensity of critical care management as measured by hospital length of stay.
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number
        median (inter-quartile range (Q1-Q3))
    23 (17 to 31)
    24 (16 to 31)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.771
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: 9. Intensity of Critical Care Management - ICU Days

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    End point title
    		 9. Intensity of Critical Care Management - ICU Days
    End point description
    Intensity of critical care management as measured by ICU length of stay.
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number
        median (inter-quartile range (Q1-Q3))
    14 (11 to 21)
    15 (12 to 22)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: 10. Intensity of Critical Care Management - ICP Management

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    End point title
    		 10. Intensity of Critical Care Management - ICP Management
    End point description
    Intensity of critical care management as measured by frequency of ICP >20 mmHg events
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of events of ICP >20mmHg
    24
    26
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Generalized Linear Models
    Confidence interval

    Secondary: 11. Intensity of Critical Care Management - Mechanical Ventilation

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    End point title
    		 11. Intensity of Critical Care Management - Mechanical Ventilation
    End point description
    Intensity of Critical Care Management as measured by Mechanical Ventilation
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants with ventilation
    184
    192
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.501
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 12. Intensity of Critical Care Management - Pressors

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    End point title
    		 12. Intensity of Critical Care Management - Pressors
    End point description
    Intensity of critical care management as measured by pressors
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    60
    63
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.795
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 13. Intensity of Critical Care Management - Shunts

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    End point title
    		 13. Intensity of Critical Care Management - Shunts
    End point description
    Intensity of critical care management as measured by shunts
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    46
    44
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.784
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 14. Intensity of Critical Care Management - All Infections

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    End point title
    		 14. Intensity of Critical Care Management - All Infections
    End point description
    Intensity of Critical Care Management as measure by all infections
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    120
    127
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.592
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 15. Intensity of Critical Care Management - Pneumonia

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    End point title
    		 15. Intensity of Critical Care Management - Pneumonia
    End point description
    Intensity of Critical Care Management as measured by Pneumonia
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    65
    82
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.105
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 16. Intensity of Critical Care Management - All Infections

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    End point title
    		 16. Intensity of Critical Care Management - All Infections
    End point description
    Intensity of critical care management as measured by all infections at 180 days
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    124
    141
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.152
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 17. Safety/Mortality - Mortality Within 30 Days

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    End point title
    		 17. Safety/Mortality - Mortality Within 30 Days
    End point description
    Frequency of mortality within 30 days
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    22
    36
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.055
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.111
         upper limit
    		 0.008

    Secondary: 18. Safety/Mortality - Bacterial Brain Infections Within 30 Days

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    End point title
    		 18. Safety/Mortality - Bacterial Brain Infections Within 30 Days
    End point description
    Frequency of bacterial brain infections within 30 days
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    17
    26
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Saline Placebo v Alteplase
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.202
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.035
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.084
         upper limit
    		 0.014

    Secondary: 19. Safety/Mortality - Systematic Bleeds Within 72 Hours

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    End point title
    		 19. Safety/Mortality - Systematic Bleeds Within 72 Hours
    End point description
    Frequency of systematic bleeds within 72 hours
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    6
    5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.771
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.022
         upper limit
    		 0.03

    Secondary: 20. Safety/Mortality - Systematic Bleeds Within 30 Days

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    End point title
    		 20. Safety/Mortality - Systematic Bleeds Within 30 Days
    End point description
    Frequency of bacterial brain infections, symptomatic brain bleeds, and mortality.
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    9
    8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.811
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.028
         upper limit
    		 0.036

    Secondary: 21. Adverse and Serious Adverse Events

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    End point title
    		 21. Adverse and Serious Adverse Events
    End point description
    Assessment of number of adverse and serious adverse events by treatment group.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    114
    151
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.144
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 -0.057

    Secondary: 22. Predicting Hazards of Death by Treatment Group

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    End point title
    		 22. Predicting Hazards of Death by Treatment Group
    End point description
    Cox Proportional Hazards Model is used to predict the hazards ratio by treatment group.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    249
    251
    Units: Number of participants
    46
    73
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [17]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.86
    Notes
    [17] - Adjusted Cox Proportional Hazards Model adjusting for age, GCS, thalamus, stability ICH volume and stability IVH volume (categorical).

    Secondary: 23. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (African-American)

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    End point title
    		 23. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (African-American)
    End point description
    Assessment of modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    90 [18]
    75 [19]
    Units: Number of participants
    49
    36
    Notes
    [18] - All African American patients with non-missing data were analysed
    [19] - All African American patients with non-missing data were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.088
         upper limit
    		 0.217

    Secondary: 24. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (White)

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    End point title
    		 24. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (White)
    End point description
    Assessment of modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    143 [20]
    158 [21]
    Units: Number of participants
    62
    66
    Notes
    [20] - All White patients with non-missing data were analysed
    [21] - All White patients with non-missing data were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.781
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.096
         upper limit
    		 0.128

    Secondary: 25. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Female)

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    End point title
    		 25. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Female)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    103 [22]
    114 [23]
    Units: Number of participants
    49
    52
    Notes
    [22] - All female patients with non-missing data were analysed
    [23] - All female patients with non-missing data were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.773
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.113
         upper limit
    		 0.152

    Secondary: 26. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Male)

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    End point title
    		 26. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Male)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    143 [24]
    131 [25]
    Units: Number of participants
    68
    58
    Notes
    [24] - All male patients with non-missing data were analysed
    [25] - All male patients with non-missing data were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.587
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.085
         upper limit
    		 0.151

    Secondary: 27. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (65 Years or Under)

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    End point title
    		 27. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (65 Years or Under)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    179 [26]
    167 [27]
    Units: Number of participants
    96
    87
    Notes
    [26] - All patients 65 years and under with non-missing data were analysed
    [27] - All patients 65 years and under with non-missing data were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.775
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.121

    Secondary: 28. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (Over 65 Years)

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    End point title
    		 28. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (Over 65 Years)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    67 [28]
    78 [29]
    Units: Number of participants
    21
    23
    Notes
    [28] - All patients over 65 years with non-missing data were analysed
    [29] - All patients over 65 years with non-missing data were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.808
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.019
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.132
         upper limit
    		 0.169

    Secondary: 29. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Less Than 20ml)

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    End point title
    		 29. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Less Than 20ml)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    109 [30]
    108 [31]
    Units: Number of participants
    60
    63
    Notes
    [30] - All patients with non-missing data and IVH size less than 20ml were analysed
    [31] - All patients with non-missing data and IVH size less than 20ml were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.625
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.165
         upper limit
    		 0.099

    Secondary: 30. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (20-50ml)

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    End point title
    		 30. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (20-50ml)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    110 [32]
    109 [33]
    Units: Number of participants
    52
    42
    Notes
    [32] - All patients with non-missing data and IVH size 20-50ml were analysed
    [33] - All patients with non-missing data and IVH size 20-50ml were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.191
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.043
         upper limit
    		 0.218

    Secondary: 31. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Greater Than 50ml)

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    End point title
    		 31. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Greater Than 50ml)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    27 [34]
    28 [35]
    Units: Number of participants
    5
    5
    Notes
    [34] - All patients with non-missing data and IVH size greater than 50ml were analysed
    [35] - All patients with non-missing data and IVH size greater than 50ml were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.949
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.0066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.197
         upper limit
    		 0.211

    Secondary: 32. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Thalamic)

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    End point title
    		 32. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Thalamic)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    147 [36]
    139 [37]
    Units: Number of participants
    57
    52
    Notes
    [36] - All patients with non-missing data and thalamic clot location were analysed
    [37] - All patients with non-missing data and thalamic clot location were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.812
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.098
         upper limit
    		 0.126

    Secondary: 33. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Non-Thalamic)

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    End point title
    		 33. Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Non-Thalamic)
    End point description
    Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    99 [38]
    106 [39]
    Units: Number of participants
    60
    58
    Notes
    [38] - All patients with non-missing data and non-thalamic clot location were analysed
    [39] - All patients with non-missing data and non-thalamic clot location were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.394
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.059
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.076
         upper limit
    		 0.194

    Secondary: 34. Functional Status - Barthel Index

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    End point title
    		 34. Functional Status - Barthel Index
    End point description
    Assessment of NIHSS, Barthel Index, eGOS (dichotomy and ordinal) by group. The Barthel Index (BI) assesses ten functional tasks of daily living, and each task provides a measure for level of independence. Scores range from 0 and 100, with a higher score indicating greater independence.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    197 [40]
    170 [41]
    Units: Barthel score
        arithmetic mean (standard deviation)
    65.2 ± 37.7
    69.5 ± 35.1
    Notes
    [40] - All patients with non-missing data at 180 days were analysed
    [41] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.312
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 35. Functional Status - Participants With Extended Glasgow Outcome (eGOS) Score >=Upper Severe Disability

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    End point title
    		 35. Functional Status - Participants With Extended Glasgow Outcome (eGOS) Score >=Upper Severe Disability
    End point description
    Assessment of NIHSS, Barthel Index, eGOS (dichotomy and ordinal) by group. The extended Glasgow Outcome Scale (eGOS) is a global scale for functional outcome with eight categories: 1 - Death, 2 - Vegetative State, 3 - Lower Severe Disability, 4 - Upper Severe Disability, 5 - Lower Moderate Disability, 6 - Upper Moderate Disability, 7 - Lower Good Recovery, 8 - Upper Good Recovery.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    241 [42]
    241 [43]
    Units: % of participants with score>=4
    95
    77
    Notes
    [42] - All patients with non-missing data at 180 days were analysed
    [43] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.087
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.075
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.011
         upper limit
    		 0.16
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.064 [44]
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 2.43
    Notes
    [44] - Adjusted Multivariable Logit Model comparing eGOS scores of Upper Severe Disability or greater versus Lower Severe Disability and worse; Alteplase versus Saline
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.336 [45]
    Method
    		 Generalized ordered Logit model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.89
    Notes
    [45] - Adjusted generalized ordered logit model odds ratios for eGOS scores of Moderate Disability or worse versus Good Recovery; Alteplase versus Saline
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.783 [46]
    Method
    		 Generalized ordered Logit model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.52
    Notes
    [46] - Adjusted generalized ordered logit model odds ratios for eGOS scores of Upper Severe Disability or worse versus Moderate Disability + Good Recovery; Alteplase versus Saline

    Secondary: 36. Functional Status - National Institutes of Health Stroke Scale (NIHSS)

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    End point title
    		 36. Functional Status - National Institutes of Health Stroke Scale (NIHSS)
    End point description
    Assessment of NIHSS, Barthel Index, eGOS (dichotomy and ordinal) by group. The National Institutes of Health Stroke Scale (NIHSS) is a 15-item scale that assesses language, motor function, sensory loss, consciousness, visual fields, extraocular movements, coordination, neglect, and speech. It is scored from 0 (no stroke symptoms) to 42 (severe stroke).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    182 [47]
    158 [48]
    Units: NIHSS score
        median (inter-quartile range (Q1-Q3))
    3 (0 to 9)
    2 (0 to 7)
    Notes
    [47] - All patients with non-missing data at 180 days were analysed
    [48] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 37. Quality of Life - Stroke Impact Scale (SIS) - Strength

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    End point title
    		 37. Quality of Life - Stroke Impact Scale (SIS) - Strength
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    186 [49]
    165 [50]
    Units: SIS score
        arithmetic mean (standard deviation)
    54.97 ± 35.37
    58.75 ± 34.36
    Notes
    [49] - All patients with non-missing data at 180 days were analysed
    [50] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.312
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 38. Quality of Life - Stroke Impact Scale (SIS) - Mobility

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    End point title
    		 38. Quality of Life - Stroke Impact Scale (SIS) - Mobility
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    186 [51]
    165 [52]
    Units: SIS score
        arithmetic mean (standard deviation)
    58.3 ± 38.6
    60.1 ± 36.05
    Notes
    [51] - All patients with non-missing data at 180 days were analysed
    [52] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 39. Quality of Life - Stroke Impact Scale (SIS) - Hand Function

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    End point title
    		 39. Quality of Life - Stroke Impact Scale (SIS) - Hand Function
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180- days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    186 [53]
    165 [54]
    Units: SIS score
        arithmetic mean (standard deviation)
    53.41 ± 41.86
    56.52 ± 39.69
    Notes
    [53] - All patients with non-missing data at 180 days were analysed
    [54] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.478
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 40. Quality of Life - Stroke Impact Scale (SIS) - Activities of Daily Living

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    End point title
    		 40. Quality of Life - Stroke Impact Scale (SIS) - Activities of Daily Living
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    186 [55]
    165 [56]
    Units: SIS score
        arithmetic mean (standard deviation)
    59.33 ± 37.9
    61.19 ± 34.98
    Notes
    [55] - All patients with non-missing data at 180 days were analysed
    [56] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.634
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 41. Quality of Life - Stroke Impact Scale (SIS) - Communication

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    End point title
    		 41. Quality of Life - Stroke Impact Scale (SIS) - Communication
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    185 [57]
    165 [58]
    Units: SIS score
        arithmetic mean (standard deviation)
    76.02 ± 31.47
    79.6 ± 26.76
    Notes
    [57] - All patients with non-missing data at 180 days were analysed
    [58] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.255
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 42. Quality of Life - Stroke Impact Scale (SIS) - Thinking

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    End point title
    		 42. Quality of Life - Stroke Impact Scale (SIS) - Thinking
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    185 [59]
    165 [60]
    Units: SIS score
        arithmetic mean (standard deviation)
    58.48 ± 33.11
    62.68 ± 31.18
    Notes
    [59] - All patients with non-missing data at 180 days were analysed
    [60] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.224
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 43. Quality of Life - Stroke Impact Scale (SIS) - Emotion

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    End point title
    		 43. Quality of Life - Stroke Impact Scale (SIS) - Emotion
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    185 [61]
    163 [62]
    Units: SIS score
        arithmetic mean (standard deviation)
    73.14 ± 19.62
    73.45 ± 20.24
    Notes
    [61] - All patients with non-missing data at 180 days were analysed
    [62] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.882
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 44. Quality of Life - Stroke Impact Scale (SIS) - Participation

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    End point title
    		 44. Quality of Life - Stroke Impact Scale (SIS) - Participation
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    186 [63]
    163 [64]
    Units: SIS score
        arithmetic mean (standard deviation)
    47.46 ± 33.01
    49.58 ± 33.03
    Notes
    [63] - All patients with non-missing data at 180 days were analysed
    [64] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.551
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 45. Quality of Life - Stroke Impact Scale (SIS) - Recovery

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    End point title
    		 45. Quality of Life - Stroke Impact Scale (SIS) - Recovery
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    185 [65]
    162 [66]
    Units: SIS score
        arithmetic mean (standard deviation)
    60.04 ± 26.42
    63.44 ± 25.44
    Notes
    [65] - All patients with non-missing data at 180 days were analysed
    [66] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.224
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: 46. Quality of Life - EuroQol Visual Analogue Scale (EQ-VAS)

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    End point title
    		 46. Quality of Life - EuroQol Visual Analogue Scale (EQ-VAS)
    End point description
    Assessment of SIS and EuroQol Visual Analog Scale by group. EuroQol Visual Analogue Scale (EQ-VAS) is a self-reported measure of health status. It is a marked scale where individuals draw a line to indicate their health, with end points of 0 (the worst health you can imagine) and 100 (the best health you can imagine).
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Alteplase Saline Placebo
    Number of subjects analysed
    177 [67]
    160 [68]
    Units: EuroQol score
        arithmetic mean (standard deviation)
    62.8 ± 26.0
    65.1 ± 23.3
    Notes
    [67] - All patients with non-missing data at 180 days were analysed
    [68] - All patients with non-missing data at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alteplase v Saline Placebo
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.376
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    180 days since symptom onset
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Alteplase
    Reporting group description
    		 Administration of alteplase via the intraventricular catheter Alteplase: 1.0 mg of alteplase will be administered via the intraventricular catheter every 8 hours for up to 12 doses

    Reporting group title
    Saline Placebo
    Reporting group description
    		 1 ml of normal saline administered via the intraventricular catheter Normal saline: 1 ml of normal saline will be administered via the intraventricular catheter every 8 hours for up to 12 doses

    Serious adverse events
    		 Alteplase Saline Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    114 / 249 (45.78%)
    151 / 251 (60.16%)
         number of deaths (all causes)
    46
    73
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    6 / 249 (2.41%)
    5 / 251 (1.99%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    PEG tube complication
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (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
    Cerebrovascular death (Brain death)
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death due to index bleeding event
         subjects affected / exposed
    10 / 249 (4.02%)
    21 / 251 (8.37%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 249 (0.40%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death NOS
         subjects affected / exposed
    6 / 249 (2.41%)
    8 / 251 (3.19%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome
         subjects affected / exposed
    3 / 249 (1.20%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    2 / 249 (0.80%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COPD
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryneal oedema
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    17 / 249 (6.83%)
    13 / 251 (5.18%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 249 (2.81%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    12 / 249 (4.82%)
    17 / 251 (6.77%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    4 / 249 (1.61%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnea
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal mucositis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    INR increased
         subjects affected / exposed
    0 / 249 (0.00%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Platelet count decreased
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy bleeding
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asystole
         subjects affected / exposed
    2 / 249 (0.80%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Caridac arrest
         subjects affected / exposed
    5 / 249 (2.01%)
    9 / 251 (3.59%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 9
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Congestive heart failure
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercardiac clot
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 249 (0.00%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachydysrhythmia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Takotsubo syndrome
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered mental status
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anoxic brain damage
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anoxic brain injury
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain and catheter related infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brainstorming/autonomic dysfunction
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 249 (0.00%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular death
         subjects affected / exposed
    2 / 249 (0.80%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 6
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Cognitive disturbance
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death due to index bleeding event
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    7 / 249 (2.81%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diencephalic storming
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema cerebral
         subjects affected / exposed
    3 / 249 (1.20%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extensor posturing
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herniation
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus, communicating
         subjects affected / exposed
    14 / 249 (5.62%)
    13 / 251 (5.18%)
         occurrences causally related to treatment / all
    0 / 14
    3 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus, obstructive
         subjects affected / exposed
    1 / 249 (0.40%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Intracranial abscess
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemmorhage: Catheter Tract, Enlargement
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemorrhage: Catheter Tract, new
         subjects affected / exposed
    8 / 249 (3.21%)
    7 / 251 (2.79%)
         occurrences causally related to treatment / all
    8 / 8
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemmorhage: Hematoma, subdural
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercranial hemorrhage: subarachnoid space, new
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemorrhage: Tissue, enlargement
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemorrhage: Tissue, new
         subjects affected / exposed
    2 / 249 (0.80%)
    5 / 251 (1.99%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemorrhage: Ventricular system, enlargement
         subjects affected / exposed
    3 / 249 (1.20%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hemorrhage: Ventricular system, new
         subjects affected / exposed
    2 / 249 (0.80%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Intracranial hypertension
         subjects affected / exposed
    9 / 249 (3.61%)
    8 / 251 (3.19%)
         occurrences causally related to treatment / all
    3 / 9
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemia cerobrovascular
         subjects affected / exposed
    3 / 249 (1.20%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    2 / 249 (0.80%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reversible cerebral vasoconstriction vs vasculitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 249 (1.20%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    4 / 249 (1.61%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    VP shunt dysfunction
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasoplasm or DIND
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventriculitis, bacterial
         subjects affected / exposed
    3 / 249 (1.20%)
    10 / 251 (3.98%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventriculitis, non-bacterial
         subjects affected / exposed
    4 / 249 (1.61%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 249 (0.80%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colonic perforation
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Hemorrhage
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal hemorrhage
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroparesis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal hemorrhage
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Swollen tongue
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intrahepatic cholestasis of unknown etiology
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         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
    Rash acneiform
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial nephritis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal calculi
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal insufficiency
         subjects affected / exposed
    6 / 249 (2.41%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chest wall pain
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness, left-sided
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal infection
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    11 / 249 (4.42%)
    7 / 251 (2.79%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 249 (1.20%)
    8 / 251 (3.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventriculitis, bacterial
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventriculitis, non-bacterial
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection, non-neurologic
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus, Type I
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatremia
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycemia
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Alteplase Saline Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    165 / 249 (66.27%)
    178 / 251 (70.92%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    21 / 249 (8.43%)
    20 / 251 (7.97%)
         occurrences all number
    21
    20
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    6 / 249 (2.41%)
    12 / 251 (4.78%)
         occurrences all number
    7
    13
    Hydrocephalus, communicating
         subjects affected / exposed
    24 / 249 (9.64%)
    33 / 251 (13.15%)
         occurrences all number
    24
    33
    Intracranial hemorrhage: Catheter tract, new
         subjects affected / exposed
    34 / 249 (13.65%)
    39 / 251 (15.54%)
         occurrences all number
    37
    47
    Intracranial hypertension
         subjects affected / exposed
    39 / 249 (15.66%)
    42 / 251 (16.73%)
         occurrences all number
    53
    50
    Seizure
         subjects affected / exposed
    13 / 249 (5.22%)
    16 / 251 (6.37%)
         occurrences all number
    14
    20
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    72 / 249 (28.92%)
    67 / 251 (26.69%)
         occurrences all number
    76
    74
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    41 / 249 (16.47%)
    53 / 251 (21.12%)
         occurrences all number
    41
    53
    Infections and infestations
    Bacteremia
         subjects affected / exposed
    13 / 249 (5.22%)
    6 / 251 (2.39%)
         occurrences all number
    13
    7
    Urinary tract infection
         subjects affected / exposed
    36 / 249 (14.46%)
    23 / 251 (9.16%)
         occurrences all number
    38
    23

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2010
    The proposed changes were as follows: • Vital signs will be recorded on the trial data capture forms less frequently (every 4 hours instead of hourly). • Follow up changes: GOS will be computed from the GOSe and not collected separately at follow up visit. EQ-SD will be collected at the 90 and 270 day telephone interviews. MMSE will be administered to all patients at days 30, 180 and 365. • Exclusion criteria changes: patients with Moya Moya disease will be excluded. Patients with INR greater than 1.3 and abnormal aPTT will also be excluded. (The INR change is due to the acceptable INR being lowered from 1.7 lo 1.3. • Acquisition of a CT angiogram is now a required part of the protocol. • Data will be captured using the VISION/Prelude EDC system. • Daily laboratory assessments of PT, fibrinogen, plasminogen and d-dimer will not take place. Fibrinogen and plasminogen will only be collected once prior to first dose. Only serum WBC,Hct, platelet count, INR, aPTTand CSF labs will be collected on a daily basis. • The need to culture the IVC tip is no longer required because the CSF is being cultured. • All quality assurance monitoring of subject data will be done remotely using the VISION/Prelude EDC system. • Analysis of video recordings of the outcome assessment of the modified Rankin scale will be undertaken by researchers from Glasgow University
    13 Jan 2011
    The proposed changes were as follows: • There has been a change in the management of the study in that the randomisation algorithm has been changed from a block randomisation to adaptive block randomisation. Details are enclosed. • The lead Neurosurgery department location in the UK has moved: Newcastle upon Tyne Hospitals NHS Foundation Trust has moved the Neurosciences Directorate from the Newcastle General Hospital to the Royal Victoria Infirmary • The Coordinating centre location has moved from the Newcastle General Hospital building to a University building: Neurosurgical Trials Unit, 3-4 Claremont Terrace, Newcastle upon Tyne NE2 4AE.
    03 Feb 2011
    The proposed change was a change of address of the site of the drug importer.
    15 May 2011
    The proposed changes were: • Addition of a new site in the UK: Salford • Updated protocol: this includes changes previously notified; an additional outcome measure; clarification of when the first dose may be given if patient safety requires additional stabilising time; a slight increase in the maximum permitted INR during screening and dosing (this will be formally analysed after the next 100 patients to ensure that it is does not significantly alter the safety of the subjects); permit the use of heparin during the acute treatment period to comply with standard of care policies (this will be formally analysed after the next 100 patients to check whether it significantly alters the safety of subjects); increased stability period from 12 to 24 hours being consistent with study training. • CTA file has been converted from version 7, additional fields completed, Prelude Dynamics has been moved from "Central Technical Facilities" classification to "Organisations to whom sponsor has transferred" as being more appropriate and Newcastle University has been added as undertaking these submissions.
    23 Apr 2013
    Currently this trial uses Cathflo Activase from Genentech imported from the USA and distributed to sites in Europe by Mawdsleys. A problem has arisen with respect to drug supply and it has become necessary to obtain the tP-A from an alternative source for use from 1st May 2013. Although this may be temporary it would be appropriate to arrange that the drug can be used from either source from now on. This alternative source is Boehringer lngelheim based in Germany (Boehringer lngelheim Pharma GmbH & Co. KG, Binger Strasse 173, 55216 lngelheim am Rhein) and the product is Actilyse Cathflo 2mg (ATC code B01AD02) with a marketing authorisation number 79189.00.00. Mawdsleys will remain responsible for the importation and distribution of drug to recruiting hospitals. The most recent version of the protocol does not specify the source of the drug. At present we only have the SPC available in German but this will be translated into English for distribution to sites. Appropriate labels have been developed by Mawdsley.
    15 May 2013
    Updated protocol includes mostly administrative clarifications. There are also some administrative corrections and changes to remove product line references, making the protocol generic, changes in timing of CT scans to align with current training and practice, amendment to exclude patients taking Dabigatran, extending the permitted interventions for DVT prophylaxis to include enoxaparin as well as other LMWH.
    29 Jul 2014
    The proposed amendment is to additionally exclude patients taking Apixaban or Rivaroxaban as well as Dabigatran.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28081952
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