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    Clinical Trial Results:
    Minimally Invasive Surgery plus rt-PA for ICH Evacuation

    Summary
    EudraCT number
    		 2007-006006-22
    Trial protocol
    		 GB   DE  
    Global end of trial date
    08 Apr 2013

    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
    ICH01
    Additional study identifiers
    ISRCTN number
    		 ISRCTN00224770
    US NCT number
    		 NCT00224770
    WHO universal trial number (UTN)
    		 -
    Sponsors
    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
    Sponsor organisation name
    Newcastle upon Tyne Hospitals NHS Trust
    Sponsor organisation address
    Joint Research Office, R&D Dept, 4th Floor, Leazes Wing, Royal Victoria Infirmary, Queen Victoria Ro, Newcastle upon Tyne, United Kingdom, NE1 4LP
    Public contact
    Amanda Tortice, Newcastle upon Tyne Hospitals NHS Trust , 0191 282 5959, amanda.tortice@nuth.nhs.uk
    Scientific contact
    Amanda Tortice, Newcastle upon Tyne Hospitals NHS Trust , 0191 282 5959, amanda.tortice@nuth.nhs.uk
    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
    02 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety of minimally invasive surgery plus aspiration followed by the administration of a low dose of recombinant tissue plasminogen activator (rt-PA; Activase, Genentech, Inc., San Francisco, CA) to intracerebral hemorrhage patients (ICH) via a catheter inserted directly into the clot and to assess its ability to remove blood clot from the brain tissue
    Protection of trial subjects
    The risks of initial haematoma growth/instability were managed by use of a stability protocol combining normalization of coagulation parameters, BP management, and repeat computed tomography (CT) assessment of clot size, measured using the ABC/2 method. Six or more hours after the diagnostic CT, a stability CT was performed to ensure that the ICH clot had not expanded by >5 mL, providing image demonstration of a safe starting point for clot reduction therapy, defined as the absence of active bleeding before performing MIS+rt-PA. The CT could be repeated every six hours until the clot stabilized or just before the 48-hour eligibility window closed, whichever came first. In addition, a magnetic resonance image (MRI) or CT angiography (CTA) was required to rule out underlying pathology as the bleeding source; an angiogram was encouraged with equivocal findings on vascular pathology screening. An INR ≤1.3, a normal aPTT, and BP stability were required prior to randomization. After a protocol amendment, planned catheter insertion trajectories describing the skull entry site and the planned linear path to the hematoma target were shared by the site with the trial’s Surgical Center for joint review (stage two only).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2006
    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
    United States: 108
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    110
    EEA total number of subjects
    2
    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)
    52
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 110 patients were randomized to the trial, and 31 were recruited as pilot patients. The decision was made to exclude the pilot patients from the analysis

    Pre-assignment
    Screening details
    		 Each study center was required to demonstrate proficiency in the technical aspects of enrollment, stabilization, surgery, and drug administration. This proficiency was demonstrated on at least one pilot patient prior to randomization of the first patient in the investigational cohort of 110 randomized patients

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Medical Management
    Arm description
    		 Standard of care medical management as per American Heart Association (AHA) guidelines.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 MISTIE Surgical Management
    Arm description
    		 Minimally invasive surgery (MIS) with clot lysis with recombinant tissue plasminogen activator (rt-PA)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cathflo Activase
    Investigational medicinal product code
    Other name
    rtPA, Alteplase
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intracerebral use
    Dosage and administration details
    Minimally invasive surgery (MIS) with clot lysis with recombinant tissue plasminogen activator (rt-PA). MIS+Cathflo Activase (drug): The intervention is a comparison of the safety and preliminary effectiveness of investigational minimally invasive surgery to place a catheter into an intracerebral hemorrhage blood clot and subsequent administration in sequential tiers of 0.3 or 1.0mg of rt-PA, CathFlo® through the catheter once every eight hours for up to 72 hours, in addition to best medical care. This includes 54 intent-to-treat patients, and excludes 27 pilots.

    Arm title
    		 ICES Surgical Management
    Arm description
    		 Intraoperative stereotactic CT-Guided Endoscopic Surgery
    Arm type
    		 Intraoperative stereotactic CT-Guided Endoscopic S

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Medical Management MISTIE Surgical Management ICES Surgical Management
    Started
    42
    54
    14
    Completed
    38
    52
    14
    Not completed
    4
    2
    0
         Lost to follow-up
    4
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Medical Management
    Reporting group description
    		 Standard of care medical management as per American Heart Association (AHA) guidelines.

    Reporting group title
    MISTIE Surgical Management
    Reporting group description
    		 Minimally invasive surgery (MIS) with clot lysis with recombinant tissue plasminogen activator (rt-PA)

    Reporting group title
    ICES Surgical Management
    Reporting group description
    		 Intraoperative stereotactic CT-Guided Endoscopic Surgery

    Reporting group values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management Total
    Number of subjects
    		 42 54 14 110
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 18 25 9 52
        From 65-84 years
    		 24 29 5 58
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 62 (49.5 to 73) 60 (54 to 69) 59 (53.2 to 68.2) -
    Gender categorical
    Units: Subjects
        Female
    		 14 19 5 38
        Male
    		 28 35 9 72
    Region of Enrollment
    Number of enrollments by region
    Units: Subjects
        United Kingdom
    		 41 53 0 94
        United States
    		 1 1 14 16

    End points

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    End points reporting groups
    Reporting group title
    Medical Management
    Reporting group description
    		 Standard of care medical management as per American Heart Association (AHA) guidelines.

    Reporting group title
    MISTIE Surgical Management
    Reporting group description
    		 Minimally invasive surgery (MIS) with clot lysis with recombinant tissue plasminogen activator (rt-PA)

    Reporting group title
    ICES Surgical Management
    Reporting group description
    		 Intraoperative stereotactic CT-Guided Endoscopic Surgery

    Primary: Rate of Mortality

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    End point title
    		 Rate of Mortality
    End point description
    Percentage of participants who died during the first 30 days after randomization.
    End point type
    Primary
    End point timeframe
    30 days from randomization
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    42
    54
    14
    Units: Percentage of participants
        number (confidence interval 90%)
    9.5 (3.3 to 20.5)
    14.8 (7.6 to 25.1)
    7.1 (0.4 to 29.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that rate of mortality within 30 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of mortality than the medical arm.
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.324
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 16.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.6
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Null hypothesis is that rate of mortality within 30 days is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher rate of mortality than the medical arm.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.633
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 11.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.2

    Primary: Rate of Procedure-related Mortality

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    End point title
    		 Rate of Procedure-related Mortality
    End point description
    Percentage of participants who died during the first 7 days after randomization.
    End point type
    Primary
    End point timeframe
    7 days from randomization
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    42
    54
    14
    Units: Percentage of particpants
        number (confidence interval 90%)
    0 (0 to 6.9)
    5.6 (1.5 to 13.7)
    0 (0 to 19.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.174
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 11.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1

    Primary: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis

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    End point title
    		 Rate of Cerebritis, Meningitis, Bacterial Ventriculitis
    End point description
    Percentage of participants who had a bacterial brain infection (cerebritis, meningitis, ventriculitis) within 30 days of randomization.
    End point type
    Primary
    End point timeframe
    30 days from randomization
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    42
    54
    14
    Units: Percentage of participants
        number (confidence interval 90%)
    2.4 (0.1 to 10.8)
    0 (0 to 5.4)
    0 (0 to 19.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that rate of cerebritis, meningitis and ventriculitis within 30 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of these infections than medical.
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.437
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Null hypothesis is that rate of cerebritis, meningitis and ventriculitis within 30 days is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher rate of these infections than medical.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4

    Primary: Rate of symptomatic rebleeding

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    End point title
    		 Rate of symptomatic rebleeding
    End point description
    The difference in the rate of symptomatic rebleeding 72 hours post last dose.
    End point type
    Primary
    End point timeframe
    72 hours post last dose
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    42
    54
    14
    Units: Percentage of participants
        number (confidence interval 90%)
    2.4 (0.1 to 10.8)
    5.6 (1.5 to 13.7)
    0 (0 to 19.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that rate of symptomatic rebleeding 72 hours post last dose is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of symptomatic rebleeding than the medical arm.
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.409
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 9.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.9
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Null hypothesis is that rate of symptomatic rebleeding 72 hours post last dose is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher rate of symptomatic rebleeding than the medical arm.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4

    Primary: Dichotomized Modified Rankin Scale (mRS) at day 180

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    End point title
    		 Dichotomized Modified Rankin Scale (mRS) at day 180
    End point description
    Percentage of participants with dichotomized mRS score in 0-3 range. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead
    End point type
    Primary
    End point timeframe
    180 days from randomization
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    38 [1]
    52 [2]
    14
    Units: Percentage of participants
        number (confidence interval 90%)
    23.7 (12.9 to 37.7)
    34.6 (23.7 to 46.9)
    42.9 (20.6 to 67.5)
    Notes
    [1] - All patients with non-missing mRS score at 180 days were analysed
    [2] - All patients with non-missing mRS score at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that the proportion with mRS score of 0-3 at 180 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher proportion than the medical arm.
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.189
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    10.9
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 26.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.5
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Null hypothesis is that the proportion with mRS score of 0-3 at 180 days is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher proportion than the medical arm.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.156
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    19.2
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 43.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.9

    Secondary: Ordinal Modified Rankin Scale (mRS) at Day 180

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    End point title
    		 Ordinal Modified Rankin Scale (mRS) at Day 180
    End point description
    Ordinal distribution of the Modified Rankin Scale score at 180 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead.
    End point type
    Secondary
    End point timeframe
    180 days from randomization
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    38 [3]
    52 [4]
    14
    Units: Unit on a scale
        median (inter-quartile range (Q1-Q3))
    4 (4 to 6)
    4 (3 to 6)
    4 (3 to 5)
    Notes
    [3] - All patients with non-missing mRS scores at 180 days were analysed
    [4] - All patients with non-missing mRS scores at 180 days were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.
    Comparison groups
    MISTIE Surgical Management v Medical Management
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.468
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    are the same. The alternative hypothesis is that the distributions are not the same.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.294
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Ordinal Modified Rankin Scale (mRS) at Day 365

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    End point title
    		 Ordinal Modified Rankin Scale (mRS) at Day 365
    End point description
    Ordinal distribution of the Modified Rankin Scale score at 365 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead.
    End point type
    Secondary
    End point timeframe
    365 days from randomization
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    24 [5]
    20 [6]
    12 [7]
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    4.5 (3.5 to 6)
    4 (2 to 6)
    3.5 (3 to 5)
    Notes
    [5] - All patients with non-missing mRS score at day 365 were analysed
    [6] - All patients with non-missing mRS score at day 365 were analysed
    [7] - All patients with non-missing mRS score at day 365 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.395 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Two-sided test
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.175 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - Two-sided test

    Secondary: Clot size reduction by end of treatment

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    End point title
    		 Clot size reduction by end of treatment
    End point description
    The percentage of blood clot resolved by the end of treatment CT scan compared to the stability CT scan.
    End point type
    Secondary
    End point timeframe
    Time from randomization until end of treatment, up to 10 days
    End point values
    		 Medical Management MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    42
    54
    14
    Units: percentage of blood clot resolved
        median (inter-quartile range (Q1-Q3))
    3.9 (-0.06 to 10.2)
    64.3 (43.3 to 74.1)
    69.5 (59.0 to 86.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis is that the distributions of percentage of blood clot resolved are the same between the two groups. The alternative hypothesis is that the distributions are not the same.
    Comparison groups
    Medical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - Two-sided test
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Null hypothesis is that the distributions of percentage of blood clot resolved are the same between the two groups. The alternative hypothesis is that the distributions are not the same.
    Comparison groups
    Medical Management v ICES Surgical Management
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Two-sided test

    Secondary: Post-operative clot size reduction among surgical patients

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    End point title
    		 Post-operative clot size reduction among surgical patients [12]
    End point description
    The percentage of blood clot resolved by the end of treatment CT scan compared to the post-operative CT scan for MISTIE surgical patients.
    End point type
    Secondary
    End point timeframe
    Time from post-operation until end of treatment, up to 10 days
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point description says "Post-operative clot size reduction among surgical patients", and this analysis relevant to Mistie surgical and ICES surgical groups. Therefore medical patients were not included in this end point analysis.
    End point values
    		 MISTIE Surgical Management ICES Surgical Management
    Number of subjects analysed
    54
    14
    Units: Percentage of blood clot resolved
        median (inter-quartile range (Q1-Q3))
    56.7 (23.6 to 68.4)
    -6.4 (-21.3 to 4.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ICES Surgical Management v MISTIE Surgical Management
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Sign test
    Confidence interval
    Notes
    [13] - Two-sided test
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    MISTIE Surgical Management v ICES Surgical Management
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.791
    Method
    		 Sign test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Medical Management
    Reporting group description
    		 -

    Reporting group title
    Mistie Surgical Management
    Reporting group description
    		 -

    Reporting group title
    ICES Surgical Management
    Reporting group description
    		 -

    Serious adverse events
    		 Medical Management Mistie Surgical Management ICES Surgical Management
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 42 (54.76%)
    28 / 54 (51.85%)
    6 / 14 (42.86%)
         number of deaths (all causes)
    7
    12
    7
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Left renal mass
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraoperative hemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 54 (3.70%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 54 (1.85%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PVC's, bigemeny
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Anoxic brain injury
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Edema cerebral
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herniation
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hemorrhage:Catheter tract, Enlargement
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hemorrhage: Catheter trace, New
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hemorrhage: Tissue, Enlargement
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hemorrhage: Tissue, New
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 54 (3.70%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intracranial hemorrhage:ventricular system, Enlargement
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hemorrhage: ventricular system, New
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hypertension
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 54 (3.70%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ischemia Cerebrovascular
         subjects affected / exposed
    4 / 42 (9.52%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnelence
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 54 (1.85%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    Sudden death
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 54 (9.26%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 42 (11.90%)
    6 / 54 (11.11%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    0 / 0
    Ventilatory failure
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Infections and infestations
    Bacteremia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehyration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Medical Management Mistie Surgical Management ICES Surgical Management
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 42 (57.14%)
    41 / 54 (75.93%)
    8 / 14 (57.14%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 42 (9.52%)
    6 / 54 (11.11%)
    0 / 14 (0.00%)
         occurrences all number
    4
    6
    0
    Hypotension
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    5
    0
    Thromboembolic event
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 54 (9.26%)
    0 / 14 (0.00%)
         occurrences all number
    1
    5
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences all number
    2
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 54 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Intracranial hemorrhage: Catheter Tract, Enlargement
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    4
    0
    Intracranial hemorrhage: Catheter Tract, New
         subjects affected / exposed
    0 / 42 (0.00%)
    6 / 54 (11.11%)
    0 / 14 (0.00%)
         occurrences all number
    0
    6
    0
    Intracranial hemorrhage: Tissue, Enlargement
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    4
    0
    Intracranial hemorrhage: Ventricular system, Enlargement
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    3
    0
    Seizure
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    5
    4
    0
    Wound closure after serious fluid leak
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 42 (0.00%)
    8 / 54 (14.81%)
    0 / 14 (0.00%)
         occurrences all number
    0
    11
    0
    Leukocytosis
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    1
    4
    0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    6 / 42 (14.29%)
    13 / 54 (24.07%)
    3 / 14 (21.43%)
         occurrences all number
    6
    14
    3
    HCAP
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 54 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Localized edema
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    3
    0
    Pain
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 54 (3.70%)
    0 / 14 (0.00%)
         occurrences all number
    2
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 42 (0.00%)
    5 / 54 (9.26%)
    1 / 14 (7.14%)
         occurrences all number
    0
    6
    1
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    5 / 42 (11.90%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences all number
    5
    1
    0
    Atelectasis
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    0
    Pleural effusion
         subjects affected / exposed
    0 / 42 (0.00%)
    5 / 54 (9.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    5
    0
    Pneumonitis
         subjects affected / exposed
    7 / 42 (16.67%)
    6 / 54 (11.11%)
    2 / 14 (14.29%)
         occurrences all number
    7
    6
    2
    Ventilatory failure
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    0
    Hematuria
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences all number
    2
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 54 (1.85%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 42 (11.90%)
    9 / 54 (16.67%)
    0 / 14 (0.00%)
         occurrences all number
    6
    9
    0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    1
    4
    0
    Hyperkalemia
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    0
    3
    0
    Hypernatremia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    0
    4
    0
    Hypocalcemia
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    2
    4
    0
    Hypoglycemia
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 54 (1.85%)
    0 / 14 (0.00%)
         occurrences all number
    3
    1
    0
    Hypokalemia
         subjects affected / exposed
    1 / 42 (2.38%)
    6 / 54 (11.11%)
    0 / 14 (0.00%)
         occurrences all number
    1
    6
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 54 (5.56%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    0
    Hyponatremia
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    1
    4
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 54 (7.41%)
    0 / 14 (0.00%)
         occurrences all number
    0
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2009
    The main changes to the protocol submitted on 12 March, 2009 relate to the addition of a new tier called Tier 3 (the ICES procedure). Tier 3 however will not be carried out in the UK or Europe (i.e. it is only to be conducted in the USA). The most important key change affecting the UK and European sites relates to a reduction in study drug dose tiers where two rt-PA doses (0.3 and 1mg) will now be tested as opposed to 3 doses (0.3, 1 and 3 mg). Since the 3mg dose is not to be used, we believe that UK and European study participants will experience less trial related risks. Additionally, there has been a change in the dosing endpoint so that rt-PA administration should continue until the residual clot is 10cc rather than 15cc (or 20% of the clot volume). The project will now run for 6 years as opposed to 4 years and each patient will be monitored for 5 days post test intervention (6 days post medical intervention) as opposed to 10 days regardless of treatment.
    17 May 2009
    Version 7 changes submitted on 9 April, 2009 are as follows: More detailed guidance has been developed in order to assist surgeons to place the catheters more accurately and hence improve the efficacy of clot removal. A new policy has been developed to allow placement of a second catheter where appropriate. Again, this should improve the efficacy of clot removal in certain cases. Additional follow up visits have been proposed at 9 and 12 months because preliminary data suggests that improvement can occur after the originally proposed 6 month time point. A decision has now been made to use the dose of 1mg t-PA. This has been established as the optimal dose following analysis of the preliminary stages of the trial. The exclusion criteria have been updated to conform to current practices (an INR > 1.3 is now regarded as an exclusion criteria - changed from 1.7), to include Moyamoya disease as a specific type of arteriovenous malformation that excludes potentially eligible patients. ln addition exclusion criteria that duplicated inclusion criteria were deleted. There have been a number of further small changes which are for administrative clarification only and which hence improve the clarity of the protocol from a reader's perspective.
    25 Feb 2011
    Version 7 changes submitted on 13 January 2011 are as follows: 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 lnfirmary. 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. A change of address of the site of the drug importer.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Aug 2009
    After stage one enrollment and DSMB review were completed, a planned protocol amendment, occurred. This specified the use of alteplase at the selected 1 mg dose (based on safety profile and clot removal efficiency), use of a surgical oversight center (based on initial surgical performance) and addition of 365 day outcome assessments. This amendment was reviewed and approved by the DSMB and executive committee. Stage two remained stratified by size, used 1:1 randomization and evaluated the safety of treatment vs. medical management.
    21 Dec 2009

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No significant limitations occurred. All limitations are summarized in the publication

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27758940
    http://www.ncbi.nlm.nih.gov/pubmed/27751554
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