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    Clinical Trial Results:
    A phase III, randomized, open-label, 500-subject clinical trial of minimally invasive surgery plus rt-PA in the treatment of intracerebral haemorrhage.

    Summary
    EudraCT number
    		 2013-002818-12
    Trial protocol
    		 GB   HU   ES   DE  
    Global end of trial date
    28 Jan 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ICH02
    Additional study identifiers
    ISRCTN number
    		 ISRCTN81927110
    US NCT number
    		 NCT01827046
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 8523
    Sponsors
    Sponsor organisation name
    Newcastle University
    Sponsor organisation address
    Wolfson Research Centre, Newcastle upon Tyne, United Kingdom, NE4 5PL
    Public contact
    Dr Barbara Gregson, Newcastle University, +44 01912085793, barbara.gregson@ncl.ac.uk
    Scientific contact
    Dr Barbara Gregson, Newcastle University, +44 01912085793, 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 Hanley, MD, Johns Hopkins University, +1 410-361-7999, dhanley@jhmi.edu
    Scientific contact
    Daniel Hanley, MD, Johns Hopkins University, +1 410-361-7999, dhanley@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
    04 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show whether minimally invasive surgery (MIS) plus recombinant tissue plasminogen activator (rt-PA) for three days improves outcome at six months as compared to standard medical treatment in patients with spontaneous bleeding in the brain (with no underlying cause)(ICH). It will also show whether early use of MIS+rt-PA for three days is safe for the treatment of ICH relative to rates of mortality, rebleeding, and infection in the medically treated subject at 30 days.
    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
    01 Dec 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety, 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
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    China: 10
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    United States: 393
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 16
    Worldwide total number of subjects
    499
    EEA total number of subjects
    78
    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)
    295
    From 65 to 84 years
    199
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment and randomization occurred at 78 hospitals in USA, Canada, Europe, Australia, and Asia

    Pre-assignment
    Screening details
    		 After screening for eligibility, patients were randomised using a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Study personnel were masked to outcome, which was determined by an adjudication committee masked to treatment allocation

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MIS plus rt-PA management
    Arm description
    		 Subjects randomized to the Minimally Invasive Surgery (MIS) plus rt-PA management arm will undergo minimally invasive surgery followed by up to 9 doses of 1.0 mg of rt-PA
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cathflo
    Investigational medicinal product code
    Other name
    Alteplase, Activase
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intracerebral use
    Dosage and administration details
    Up to 9 doses of 1.0 mg of rt-PA will be administered through the catheter that was placed directly into the intracerebral hemorrhage using minimally invasive surgery.

    Arm title
    		 Medical Management
    Arm description
    		 Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		MIS plus rt-PA management Medical Management
    Started
    250
    249
    Completed
    249
    240
    Not completed
    1
    9
         Consent withdrawn by subject
    -
    4
         Lost to follow-up
    1
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MIS plus rt-PA management
    Reporting group description
    		 Subjects randomized to the Minimally Invasive Surgery (MIS) plus rt-PA management arm will undergo minimally invasive surgery followed by up to 9 doses of 1.0 mg of rt-PA

    Reporting group title
    Medical Management
    Reporting group description
    		 Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.

    Reporting group values
    		 MIS plus rt-PA management Medical Management Total
    Number of subjects
    		 250 249 499
    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)
    		 146 149 295
        From 65-84 years
    		 104 95 199
        85 years and over
    		 0 5 5
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 62 (52 to 70) 62 (53 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 91 103 194
        Male
    		 159 146 305
    Race
    Units: Subjects
        American Indian or alaska Native
    		 1 1 2
        Asian
    		 12 18 30
        Native Hawaiian or other Pacifiec Islander
    		 0 3 3
        Black or African american
    		 46 41 87
        White
    		 190 184 374
        More than one race
    		 0 2 2
        Unknown or Not reported
    		 1 0 1
    Region of enrollment
    Units: Subjects
        Australia
    		 2 2 4
        Canada
    		 3 4 7
        China
    		 5 5 10
        Germany
    		 4 4 8
        Spain
    		 10 12 22
        Great Britain
    		 16 16 32
        Hungary
    		 8 8 16
        Israel
    		 3 4 7
        United States
    		 199 194 393
    Tobacco use
    Units: Subjects
        Yes
    		 50 39 89
        No
    		 200 210 410
    Cocaine use
    Units: Subjects
        Yes
    		 11 9 20
        No
    		 239 240 479
    On anticoagulants
    Units: Subjects
        Yes
    		 24 10 34
        No
    		 226 239 465
    Use of Hormone replacement therapy
    Units: Subjects
        Yes
    		 1 3 4
        No
    		 249 246 495
    Hyperlipidaemia medication compliant
    Units: Subjects
        Yes
    		 96 93 189
        No
    		 154 156 310
    On antiplatelet therapy
    Units: Subjects
        Yes
    		 67 77 144
        No
    		 183 172 355
    History of diabetes
    Units: Subjects
        Yes
    		 72 67 139
        No
    		 178 182 360
    History of hypertension
    Units: Subjects
        Yes
    		 241 240 481
        No
    		 9 9 18
    Other cardiovascular disease
    Units: Subjects
        Yes
    		 38 34 72
        No
    		 212 215 427
    GCS score at randomisation
    Glasgow Coma Scale (GCS) scores range from 15 (fully conscious) to 3 (Deep coma)
    Units: Subjects
        3-8
    		 64 63 127
        9-12
    		 111 108 219
        13-15
    		 75 78 153
    Ventilated at randomisation
    Units: Subjects
        Yes
    		 107 102 209
        No
    		 143 147 290
    mRS score before stroke
    Measure Description: Score 0 = No symptoms. Score 1 = Having symptoms but no significant disability, and is able to carry out all usual activities
    Units: Subjects
        No symptoms
    		 230 233 463
        Having symptoms but no significant disability
    		 20 16 36
    Clot location
    Units: Subjects
        Deep
    		 163 144 307
        Lobar
    		 87 105 192
    NIHSS score at randomisation
    NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The maximum possible score is 42, with the minimum score being 0. Stroke severity is scored in the following way:0=No stroke symptoms,1-4=Minor stroke, 5-15=Moderate stroke,16- 20=Moderate to severe stroke, 21-42=Severe stroke
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    		 19 (15 to 23) 19 (15 to 23) -
    Diagnostic CT at presentation - IntraCerebral Hemorrhage (ICH) volume
    Units: mL
        median (inter-quartile range (Q1-Q3))
    		 42.7 (30.4 to 54.5) 41.5 (30.9 to 55.3) -
    Diagnostic CT at presentation - IntraVentricular Hemorrhage (IVH) volume
    Units: mL
        median (inter-quartile range (Q1-Q3))
    		 0 (0 to 1.7) 0 (0 to 1.9) -
    Stability CT (last CT before randomisation) - IntraCerebral Hemorrhage (ICH) volume
    Units: mL
        median (inter-quartile range (Q1-Q3))
    		 45.8 (35.4 to 59.6) 45.3 (35.4 to 57.2) -
    Stability CT (last CT before randomisation) - IntraVentricular Hemorrhage (IVH) volume
    Units: mL
        median (inter-quartile range (Q1-Q3))
    		 0.3 (0 to 3.1) 0.4 (0 to 3.2) -
    Systolic blood pressure at presentation
    Units: mm Hg
        median (inter-quartile range (Q1-Q3))
    		 177 (155 to 208) 176 (158 to 200) -
    Diastolic blood pressure at presentation
    Units: mm Hg
        median (inter-quartile range (Q1-Q3))
    		 99 (85 to 113) 98 (84 to 114) -
    Systolic blood pressure at randomisation
    Units: mm Hg
        median (inter-quartile range (Q1-Q3))
    		 138 (130 to 148) 138 (131 to 148) -
    Diastolic blood pressure at randomisation
    Units: mm Hg
        median (inter-quartile range (Q1-Q3))
    		 70 (63 to 78) 69 (60 to 77) -
    Time from stroke to diagnostic CT
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    		 2.2 (1.1 to 6.0) 1.9 (1.2 to 4.8) -
    Time from stroke to stability CT
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    		 36.4 (23.4 to 52.6) 36.3 (23.6 to 48.6) -

    End points

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    End points reporting groups
    Reporting group title
    MIS plus rt-PA management
    Reporting group description
    		 Subjects randomized to the Minimally Invasive Surgery (MIS) plus rt-PA management arm will undergo minimally invasive surgery followed by up to 9 doses of 1.0 mg of rt-PA

    Reporting group title
    Medical Management
    Reporting group description
    		 Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.

    Primary: 1.Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)

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    End point title
    		 1.Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)
    End point description
    Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 365 days post-ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). Ictus refers to symptom onset. 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-No symptoms at all, 1=No significant disability, 2=Slight disability, 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
    Day 365
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    249 [1]
    240 [2]
    Units: Number of participants
        mRS 0-3
    110
    100
        mRS 4-6
    139
    140
    Notes
    [1] - Includes participants with mRS scores available at day 365.
    [2] - Includes participants with mRS scores available at day 365.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 10.7
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted for age, GCS, stability ICH volume, stability IVH volume, ICH deep location
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 12

    Secondary: 2. Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)

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    End point title
    		 2. Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)
    End point description
    Dichotomized, cross-sectional extended Glasgow Outcome Scale (eGOS) score upper good recovery (UGR) through upper severe disability (US) vs. lower severe disability (LS) through death at 365 days post ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). The eGOS 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 as: 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. Dichotomous variable coding is as follows: 1=codes 4-8, 0=codes 1-3.
    End point type
    Secondary
    End point timeframe
    Day 365
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    244 [3]
    234 [4]
    Units: Number of participants
        eGOS UGR-US (4-8)
    94
    84
        eGOS LS-Death (1-3)
    150
    150
    Notes
    [3] - Those with non-missing mRS scores at 365 days post ictus
    [4] - Those with non-missing mRS scores at 365 days post ictus
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.11
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Multivariate logit model adjusted for age, GCS, stability ICH volume, stability IVH volume and ICH deep location
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.97

    Secondary: 3. All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)

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    End point title
    		 3. All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)
    End point description
    By group comparison of mortality from ictus to 365 days adjusted for baseline severity.
    End point type
    Secondary
    End point timeframe
    Day 365
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of participants
    48
    62
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted Cox proportional Hazard adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location, diabetes, cardiovascular disease and race.
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 Adjusted cox proportional hazard
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.98

    Secondary: 4. Clot Removal (Amount of Residual Blood)

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    End point title
    		 4. Clot Removal (Amount of Residual Blood)
    End point description
    Relationship between clot removal as an Area Under the Curve (AUC) clot assessment that estimates the time-averaged clot volume from ictus to end of treatment (EOT i.e. 24 hours after last dose) as AUC clot exposure and functional outcome (proportion 0-3 Modified Rankin Scale (mRS)).
    End point type
    Secondary
    End point timeframe
    24 hours after last dose
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    246 [5]
    239 [6]
    Units: 10mL x days
    arithmetic mean (standard deviation)
        mRS 0-3
    2.69 ( 1.11 )
    4.11 ( 1.35 )
        mRS 4-6
    3.32 ( 1.33 )
    5.26 ( 1.82 )
    Notes
    [5] - Includes patients who survived through the dosing period
    [6] - Includes patients who survived through the dosing period
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Medical Management v MIS plus rt-PA management
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logit model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.8
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.78

    Secondary: 5. Patient Disposition: Home Days Over 365 Days Time From Ictus.

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    End point title
    		 5. Patient Disposition: Home Days Over 365 Days Time From Ictus.
    End point description
    By group comparison of cumulative days at home during the 365 days post ictus.
    End point type
    Secondary
    End point timeframe
    During 365 days of follow-up
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    166 [7]
    157 [8]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    306 (237 to 329)
    300 (232 to 328)
    Notes
    [7] - Includes only patients with cumulative home days at any time during the 365 days of followup.
    [8] - Includes only patients with cumulative home days at any time during the 365 days of followup.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 6. Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)

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    End point title
    		 6. Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)
    End point description
    Patient disposition: By group comparison of residential location at day 365 post ictus adjusted for baseline severity. Good locations refers to home and rehabilitation; and bad locations refers to acute care, long-term care and death.
    End point type
    Secondary
    End point timeframe
    Day 365
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    201 [9]
    178 [10]
    Units: Number of participants
        Good location
    163
    151
        Bad location
    87
    98
    Notes
    [9] - Includes patients who were alive and not lost to follow-up at day 365
    [10] - Includes patients who were alive and not lost to follow-up at day 365
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.11

    Secondary: 7. Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)

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    End point title
    		 7. Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)
    End point description
    Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 180 days post-ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). 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
    Secondary
    End point timeframe
    Day 180 post ictus
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250 [11]
    243 [12]
    Units: Number of participants
        mRS 0-3
    99
    93
        mRS 4-6
    151
    150
    Notes
    [11] - Includes patients who were not lost to followup at day 180
    [12] - Includes patients who were not lost to followup at day 180
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.07
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Multivariate logit model adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.94

    Secondary: 8. Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)

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    End point title
    		 8. Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)
    End point description
    Dichotomized, cross-sectional extended Glasgow Outcome Scale (eGOS) score upper good recovery (UGR) through upper severe disability (US) vs. lower severe disability (LS) through death at 180 days post ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). The eGOS 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 as: 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. Dichotomous variable coding is as follows: 1=codes 4-8, 0=codes 1-3.
    End point type
    Secondary
    End point timeframe
    Day 180 post ictus
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    243 [13]
    Units: Number of participants
        eGOS UGR-US (4-8)
    81
    76
        eGOS LS-Death (1-3)
    169
    167
    Notes
    [13] - Includes patients not lost to followup at day 180
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.09
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Multivariate logit model adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Multivariate Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.97

    Secondary: 9.Type and Intensity of ICU Management: ICU Days

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    End point title
    		 9.Type and Intensity of ICU Management: ICU Days
    End point description
    By group comparison of cumulative number of days in the Intensive Care Unit (ICU) in a hospital
    End point type
    Secondary
    End point timeframe
    Up to 365 days
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    240 [14]
    238 [15]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    10 (7 to 17)
    10 (5 to 16)
    Notes
    [14] - Includes patients with cumulative ICU days during the 365 days of follow-up
    [15] - Includes patients with cumulative ICU days during the 365 days of follow-up
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Median test
    Confidence interval

    Secondary: 10. Type and Intensity of ICU Management: Hospital Days

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    End point title
    		 10. Type and Intensity of ICU Management: Hospital Days
    End point description
    By group comparison of total number of days in the hospital
    End point type
    Secondary
    End point timeframe
    Up to 365 days
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Days
        median (inter-quartile range (Q1-Q3))
    17 (13 to 27)
    17 (10 to 25)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 Median test
    Confidence interval

    Secondary: 11. EQ-VAS

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    End point title
    		 11. EQ-VAS
    End point description
    By group comparison of EQ-VAS at day 365 post ictus. The EuroQol Visual Analogue Scale (EQ-VAS) is a self-reported measure of health status. It is a marked scale where subjects 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
    Day 365
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    183 [16]
    164 [17]
    Units: Score on a scale
        median (inter-quartile range (Q1-Q3))
    70 (50 to 80)
    70 (50 to 80)
    Notes
    [16] - Includes patients who survived or were not lost to followup through 365 days
    [17] - Includes patients who survived or were not lost to followup through 365 days
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 12. EuroQol 5 Dimensional Scale (EQ-5D)

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    End point title
    		 12. EuroQol 5 Dimensional Scale (EQ-5D)
    End point description
    By group comparison of EQ-5D at day 365 post ictus. The EuroQol 5 Dimensional Scale (Eq-5D) is a self-reported measure of health status. It is arranged to assess domains related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each domain, codes were 1=no problems, 2=some problems, 3=extreme problems, and 9=unknown. Having a problem in at least 1 domain was coded as 1 (originally represented by 2 or 3) and no problems as 0 (originally represented by 1)
    End point type
    Secondary
    End point timeframe
    Day 365
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    192 [18]
    170 [19]
    Units: Number of participants
        Any problem
    176
    155
        No problem
    16
    15
    Notes
    [18] - Includes patients who survived or were not lost to followup through 365 days
    [19] - Includes patients who survived or were not lost to followup through 365 days
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 13. First-week (Operative) Mortality

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    End point title
    		 13. First-week (Operative) Mortality
    End point description
    Mortality and Safety events: By group comparison of mortality within the first 7 days post randomization.
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of participants
    1
    10
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 14. All Cause Mortality

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    End point title
    		 14. All Cause Mortality
    End point description
    By group comparison of mortality from all causes within the first 30 days post randomization.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of participants
    23
    37
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 15. Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose

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    End point title
    		 15. Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose
    End point description
    By group comparison of the percentage of subjects experiencing one or more adjudicated symptomatic brain bleeding events within the first 30 days post randomization.
    End point type
    Secondary
    End point timeframe
    72 hours after last dose
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of participants
    6
    3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 16. Adjudicated Bacterial Brain Infection

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    End point title
    		 16. Adjudicated Bacterial Brain Infection
    End point description
    By group comparison of the percentage of subjects experiencing one or more adjudicated brain bacterial infection events within the first 30 days post randomization.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of participants
    2
    0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 17. Total Serious Adverse Events (SAE) at 30 Days

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    End point title
    		 17. Total Serious Adverse Events (SAE) at 30 Days
    End point description
    By group comparison of the total number of adjudicated serious adverse events that occurred within the first 30 days post randomization.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of events
    123
    136
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MIS plus rt-PA management v Medical Management
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 18. Number of Adverse Events (AEs) Within the First 30 Days Post Ictus

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    End point title
    		 18. Number of Adverse Events (AEs) Within the First 30 Days Post Ictus
    End point description
    By group comparison of the total number of adjudicated adverse events (AE) across all coded organ systems that occurred within the first 30 days post ictus.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 MIS plus rt-PA management Medical Management
    Number of subjects analysed
    250
    249
    Units: Number of events
    477
    378
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days post ictus
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    MIS plus rt-PA management
    Reporting group description
    		 Subjects randomized to the Minimally Invasive Surgery (MIS) plus rt-PA management arm will undergo minimally invasive surgery followed by up to 9 doses of 1.0 mg of rt-PA

    Reporting group title
    Medical Management
    Reporting group description
    		 Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.

    Serious adverse events
    		 MIS plus rt-PA management Medical Management
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 250 (30.00%)
    84 / 249 (33.73%)
         number of deaths (all causes)
    48
    62
         number of deaths resulting from adverse events
    24
    38
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    3 / 250 (1.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    6 / 250 (2.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    3 / 250 (1.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    17 / 250 (6.80%)
    33 / 249 (13.25%)
         occurrences causally related to treatment / all
    14 / 41
    0 / 62
         deaths causally related to treatment / all
    1 / 1
    0 / 8
    General disorders and administration site conditions
    General disorders
         subjects affected / exposed
    13 / 250 (5.20%)
    26 / 249 (10.44%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 27
         deaths causally related to treatment / all
    1 / 12
    0 / 25
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    3 / 250 (1.20%)
    4 / 249 (1.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Resoiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    26 / 250 (10.40%)
    14 / 249 (5.62%)
         occurrences causally related to treatment / all
    0 / 40
    0 / 25
         deaths causally related to treatment / all
    0 / 8
    0 / 1
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    REnal and urinary disorders
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    2 / 250 (0.80%)
    4 / 249 (1.61%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MIS plus rt-PA management Medical Management
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    205 / 250 (82.00%)
    169 / 249 (67.87%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 249 (0.40%)
         occurrences all number
    1
    2
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    14 / 250 (5.60%)
    13 / 249 (5.22%)
         occurrences all number
    39
    29
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    17 / 250 (6.80%)
    12 / 249 (4.82%)
         occurrences all number
    53
    42
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    30 / 250 (12.00%)
    33 / 249 (13.25%)
         occurrences all number
    67
    62
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    6 / 250 (2.40%)
    5 / 249 (2.01%)
         occurrences all number
    14
    13
    Investigations
    Investigations
         subjects affected / exposed
    1 / 250 (0.40%)
    7 / 249 (2.81%)
         occurrences all number
    12
    20
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 250 (0.40%)
    2 / 249 (0.80%)
         occurrences all number
    4
    3
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    3 / 250 (1.20%)
    5 / 249 (2.01%)
         occurrences all number
    15
    11
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    108 / 250 (43.20%)
    47 / 249 (18.88%)
         occurrences all number
    216
    107
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    2 / 250 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    5 / 250 (2.00%)
    7 / 249 (2.81%)
         occurrences all number
    12
    17
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    0 / 250 (0.00%)
    2 / 249 (0.80%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    3 / 250 (1.20%)
    2 / 249 (0.80%)
         occurrences all number
    5
    5
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    2 / 250 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    9 / 250 (3.60%)
    25 / 249 (10.04%)
         occurrences all number
    16
    41
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    3 / 250 (1.20%)
    6 / 249 (2.41%)
         occurrences all number
    17
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2015
    In this amendment, there are a large number of administrative clarifications; the results of other studies that have now reported have been incorporated – they do not alter the trial; the inclusion and exclusion criteria have been amended slightly removing the upper age limit, and adding etiological exclusions, and medication exclusions; a longer stability time between catheter placement and drug administration is required.; further MRI sequences have been added to the imaging. The optional substudies investigate whether certain factors observed on imaging are related to perioperative bleeding and outcome after this treatment; the relationship between inflammatory mediators and haematoma volume and outcome and finally whether specific genotypes are associated with outcome. In addition two further UK sites have been added since the initial acceptance was obtained. The contact name and address for the legal representative of the sponsor in the UK has also changed.

    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/30739747
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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