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    Clinical Trial Results:
    Phase II, randomized, pharmokinetic, dose finding, and dose frequency determination using rt-PA in intraventricular hemorrhage

    Summary
    EudraCT number
    		 2004-000919-26
    Trial protocol
    		 GB   FI  
    Global end of trial date
    21 Aug 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2020
    First version publication date
    26 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IVH05
    Additional study identifiers
    ISRCTN number
    		 ISRCTN47341677
    US NCT number
    		 NCT00650858
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Johns Hopkins University
    Sponsor organisation address
    750 E. Pratt Street, 16th Floor, Baltimore, United States, 21202
    Public contact
    Daniel F. Hanley, MD, Johns Hopkins University, +1 410-361-7999, dhanley2@jhmi.edu
    Scientific contact
    Daniel F. Hanley, MD, Johns Hopkins University, +1 410-361-7999, dhanley2@jhmi.edu
    Sponsor organisation name
    Newcastle upon Tyne Hospitals NHS Trust
    Sponsor organisation address
    RVI, Queen Victoria Road, Newcastle upon Tyne, United Kingdom, NE1 4LPE
    Public contact
    Jane Varey, Newcastle upon Tyne Hospitals NHS Trust, 0191 2825959, Trust.R&D@nuth.nhs.uk
    Scientific contact
    Jane Varey, Newcastle upon Tyne Hospitals NHS Trust, 0191 2825959, Trust.R&D@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
    31 Aug 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    CLEAR IVH, a Phase II dose-finding study, tested the ability of different doses of recombinant tissue plasminogen activator (rt-PA, Cathflo®; Genentech, Inc.) to lyse intraventricular blood clots. Subjects experiencing spontaneous intracerebral hemorrhage (ICH) with intraventricular hemorrhage (IVH) extension were enrolled according to protocol. Major selection criteria were: 1) presence of ICH ≤ 30cc; 2) acute obstructive hydrocephalus secondary to large intraventricular hemorrhage; and 3) stability of IVH and ICH size over a 6-hour period of observation with CT scanning. Pregnant women and children were not enrolled. There were no major changes to the protocol; minor changes included an increased enrollment time window and clarifications to dosage discontinuation rules.
    Protection of trial subjects
    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 6 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 6 month follow-up period 9. All infections reported to the safety and monitoring committee for an independent assessment of clinical significance
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jan 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United States: 47
    Worldwide total number of subjects
    52
    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)
    39
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment began for protocol stage 1 in August 2005 and ended for protocol stage 2 on February 6, 2008. Subjects were screened by clinical stroke service personnel in the Emergency Department or by direct transfer from an outside hospital.

    Pre-assignment
    Screening details
    		 Major selection criteria were: 1) presence of ICH ≤ 30cc; 2) acute obstructive hydrocephalus secondary to large intraventricular hemorrhage; and 3) stability of IVH and ICH size over a 6-hour period of observation with CT scanning. Pregnant women and children were not enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active Comparator: 0.3 mg rt-PA q12h
    Arm description
    		 In stage 1 of the protocol, dose finding, subjects were randomized to either this 0.3 mg dose arm or the 1.0 mg dose arm. Subjects in this arm (0.3 mg) received up to 8 doses of 0.3 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rt-PA
    Investigational medicinal product code
    Other name
    Activase, Cathflo
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intraventricular use
    Dosage and administration details
    0.3 mg and 1.0 mg of rt-PA (Cathflo) were administered every 12 hours (dose finding) and every 8 hours (dose frequency) via the intraventricular catheter to treat intraventricular hemorrhage.

    Arm title
    		 Active Comparator: 1.0 mg rt-PA q12h
    Arm description
    		 In stage 1 of the protocol, dose finding, subjects were randomized to either this 1.0 mg dose arm or the 0.3 mg dose arm. Subjects in this arm (1.0 mg) received up to 8 doses of 1.0 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rt-PA
    Investigational medicinal product code
    Other name
    Activase, Cathflo
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intraventricular use
    Dosage and administration details
    1.0 mg of rt-PA (Cathflo) were administered every 12 hours (dose finding) and every 8 hours (dose frequency) via the intraventricular catheter to treat intraventricular hemorrhage.

    Arm title
    		 Experimental: 1.0 mg rt-PA q8h
    Arm description
    		 In stage 2 of the protocol, dose frequency, subjects received up to 8 doses of 1.0 mg of rt-PA (Cathflo) every 8 hours through the intraventricular catheter to treat intraventricular hemorrhage.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rt-PA
    Investigational medicinal product code
    Other name
    Activase, Cathflo
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intraventricular use
    Dosage and administration details
    Subjects received up to 8 doses of 1.0 mg of rt-PA (Cathflo) every 8 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Number of subjects in period 1
    		Active Comparator: 0.3 mg rt-PA q12h Active Comparator: 1.0 mg rt-PA q12h Experimental: 1.0 mg rt-PA q8h
    Started
    8
    8
    36
    Completed
    8
    8
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active Comparator: 0.3 mg rt-PA q12h
    Reporting group description
    		 In stage 1 of the protocol, dose finding, subjects were randomized to either this 0.3 mg dose arm or the 1.0 mg dose arm. Subjects in this arm (0.3 mg) received up to 8 doses of 0.3 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Reporting group title
    Active Comparator: 1.0 mg rt-PA q12h
    Reporting group description
    		 In stage 1 of the protocol, dose finding, subjects were randomized to either this 1.0 mg dose arm or the 0.3 mg dose arm. Subjects in this arm (1.0 mg) received up to 8 doses of 1.0 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Reporting group title
    Experimental: 1.0 mg rt-PA q8h
    Reporting group description
    		 In stage 2 of the protocol, dose frequency, subjects received up to 8 doses of 1.0 mg of rt-PA (Cathflo) every 8 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Reporting group values
    		 Active Comparator: 0.3 mg rt-PA q12h Active Comparator: 1.0 mg rt-PA q12h Experimental: 1.0 mg rt-PA q8h Total
    Number of subjects
    		 8 8 36 52
    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)
    		 7 6 26 39
        From 65-84 years
    		 1 2 10 13
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.6 ( 9.8 ) 57.3 ( 8.3 ) 57.0 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 11 18
        Male
    		 5 4 25 34
    Region of Enrollment
    Units: Subjects
        United States
    		 8 8 31 47
        Canada
    		 0 0 3 3
        Germany
    		 0 0 1 1
        United Kingdom
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Active Comparator: 0.3 mg rt-PA q12h
    Reporting group description
    		 In stage 1 of the protocol, dose finding, subjects were randomized to either this 0.3 mg dose arm or the 1.0 mg dose arm. Subjects in this arm (0.3 mg) received up to 8 doses of 0.3 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Reporting group title
    Active Comparator: 1.0 mg rt-PA q12h
    Reporting group description
    		 In stage 1 of the protocol, dose finding, subjects were randomized to either this 1.0 mg dose arm or the 0.3 mg dose arm. Subjects in this arm (1.0 mg) received up to 8 doses of 1.0 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Reporting group title
    Experimental: 1.0 mg rt-PA q8h
    Reporting group description
    		 In stage 2 of the protocol, dose frequency, subjects received up to 8 doses of 1.0 mg of rt-PA (Cathflo) every 8 hours through the intraventricular catheter to treat intraventricular hemorrhage.

    Primary: 1. Primary: 30-day Mortality

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    End point title
    		 1. Primary: 30-day Mortality
    End point description
    The number of subjects who died at or before the 30-day follow-up visit were determined as a measure of safety. If more than 50% of the subjects died at or before the 30-day follow-up visit, the study would have been stopped for full DSMB review.
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 Active Comparator: 0.3 mg rt-PA q12h Active Comparator: 1.0 mg rt-PA q12h Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    8
    8
    36
    Units: Number of participants
    1
    1
    6
    Statistical analysis title
    		 Difference by group for 30-Day mortality
    Comparison groups
    Active Comparator: 0.3 mg rt-PA q12h v Active Comparator: 1.0 mg rt-PA q12h v Experimental: 1.0 mg rt-PA q8h
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Primary: 2. Primary: Incidence of Bacterial Ventriculitis, Meningitis

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    End point title
    		 2. Primary: Incidence of Bacterial Ventriculitis, Meningitis
    End point description
    The incidence of bacterial ventriculitis/meningitis was recorded to determine the safety of intraventricular administration of rt-PA. If 30% or more subjects experienced this event, the study would have been stopped for full DSMB review.
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 Active Comparator: 0.3 mg rt-PA q12h Active Comparator: 1.0 mg rt-PA q12h Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    8
    8
    36
    Units: Number of participants
    0
    1
    1
    Statistical analysis title
    		 Difference by group for 30-Day ventriculitis
    Comparison groups
    Active Comparator: 1.0 mg rt-PA q12h v Experimental: 1.0 mg rt-PA q8h v Active Comparator: 0.3 mg rt-PA q12h
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.525
    Method
    		 Fisher exact
    Confidence interval

    Primary: 3. Primary: Rate of symptomatic Bleeding Events

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    End point title
    		 3. Primary: Rate of symptomatic Bleeding Events
    End point description
    The rate of symptomatic brain bleeding events were recorded to determine the safety of intraventricular administrations of rt-PA. If 35% or more subjects experienced a symptomatic bleeding event prior to the 30-day follow-up visit, the study would have been stopped for a full DSMB review.
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 Active Comparator: 0.3 mg rt-PA q12h Active Comparator: 1.0 mg rt-PA q12h Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    8
    8
    36
    Units: Number of participants
    0
    0
    2
    Statistical analysis title
    		 Difference by group for 30-Day bleeding
    Comparison groups
    Active Comparator: 0.3 mg rt-PA q12h v Active Comparator: 1.0 mg rt-PA q12h v Experimental: 1.0 mg rt-PA q8h
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: 4. Secondary: Average Daily Percentage Clot Size Resolution Over the First 3 Days

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    End point title
    		 4. Secondary: Average Daily Percentage Clot Size Resolution Over the First 3 Days
    End point description
    Daily IVH clot volume resolution, as a percentage of stability CT IVH volume, averaged over the first 3 days, determined by CT scans
    End point type
    Secondary
    End point timeframe
    3 days
    End point values
    		 Active Comparator: 0.3 mg rt-PA q12h Active Comparator: 1.0 mg rt-PA q12h Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    8
    8
    36
    Units: Percent of stability CT volume resolved
        arithmetic mean (full range (min-max))
    22.19 (8 to 66)
    24.20 (0 to 72)
    19.99 (0 to 60)
    No statistical analyses for this end point

    Secondary: 5. Secondary: 90 Day Follow-up Modified Rankin Scale (mRS) Score

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    End point title
    		 5. Secondary: 90 Day Follow-up Modified Rankin Scale (mRS) Score [1]
    End point description
    End point type
    Secondary
    End point timeframe
    90 Days
    Notes
    [1] - 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: This is the median mRS score at 90 days for one treatment arm and there is no comparison group to provide a statistical result.
    End point values
    		 Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    36
    Units: mRS Score
        median (full range (min-max))
    4.3 (0 to 6)
    No statistical analyses for this end point

    Secondary: 6. Secondary: 90 Day Follow-Up Glasgow Outcome Scale (GOS) Score

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    End point title
    		 6. Secondary: 90 Day Follow-Up Glasgow Outcome Scale (GOS) Score [2]
    End point description
    90 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
    End point type
    Secondary
    End point timeframe
    90 Days
    Notes
    [2] - 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: This is the median GOS score at 90 days for one treatment arm and there is no comparison group to provide a statistical result.
    End point values
    		 Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    35 [3]
    Units: GOS Score
        median (full range (min-max))
    2.3 (0 to 4)
    Notes
    [3] - Analyzed only those with non-missing GOS score
    No statistical analyses for this end point

    Secondary: 7. Secondary: 180 Day Follow-Up Modified Rankin Scale (mRS) Score

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    End point title
    		 7. Secondary: 180 Day Follow-Up Modified Rankin Scale (mRS) Score [4]
    End point description
    180 day follow-up visit mRS score. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
    End point type
    Secondary
    End point timeframe
    180 Days
    Notes
    [4] - 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: This is the median mRS score at 180 days for one treatment arm and there is no comparison group to provide a statistical result.
    End point values
    		 Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    35 [5]
    Units: mRS Score
        median (full range (min-max))
    4.0 (0 to 6)
    Notes
    [5] - Analyzed only those with non-missing mRS score
    No statistical analyses for this end point

    Secondary: 8. Secondary: 180 Day Follow-Up Glasgow Outcome Scale (GOS) Score

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    End point title
    		 8. Secondary: 180 Day Follow-Up Glasgow Outcome Scale (GOS) Score [6]
    End point description
    180 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
    End point type
    Secondary
    End point timeframe
    180 Days
    Notes
    [6] - 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: This is the median GOS score at 180 days for one treatment arm and there is no comparison group to provide a statistical result.
    End point values
    		 Experimental: 1.0 mg rt-PA q8h
    Number of subjects analysed
    35 [7]
    Units: GOS Score
        median (full range (min-max))
    2.3 (0 to 4)
    Notes
    [7] - Analysed only those with non-missing data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During follow-up period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    0.3 mg rt-PA q12h
    Reporting group description
    		 0.3 mg of rt-PA (Cathflo) was administered every 12 hours (dose finding)

    Reporting group title
    1.0 mg rt-PA q12h
    Reporting group description
    		 1.0 mg of rt-PA (Cathflo) was administered every 12 hours (dose finding)

    Reporting group title
    1.0 mg rt-PA q8h
    Reporting group description
    		 1.0 mg of rt-PA (Cathflo) was administered every 8hours (dose frequency)

    Serious adverse events
    		 0.3 mg rt-PA q12h 1.0 mg rt-PA q12h 1.0 mg rt-PA q8h
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    11 / 36 (30.56%)
         number of deaths (all causes)
    1
    1
    10
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage new catheter tract >5 mm with mas effect, symptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus, Communicating
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    ICH Hemorrhage, new symptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IVH Hemorrhage enlargement - asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IVH Hemorrhage enlargement - symptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IVH hemorrhage, new symptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventriculitis, Bacterial
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventriculitis, Non-Bacterial
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Accidental Extubation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suspected cardiac or pulmonary embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal stricture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ventilatory failure, mechanical
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 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
    		 0.3 mg rt-PA q12h 1.0 mg rt-PA q12h 1.0 mg rt-PA q8h
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    8 / 8 (100.00%)
    32 / 36 (88.89%)
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    Bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Congestive Heart Failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 8 (37.50%)
    1 / 36 (2.78%)
         occurrences all number
    1
    4
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Brain Edema / Swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    3
    CSF Leak
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    Cerebral Infarction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    0
    5
    Cerebral infarction, extension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    Decreased Level of consciousness
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    7 / 36 (19.44%)
         occurrences all number
    3
    2
    12
    Encephalopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    0
    4
    Hemorrhage enl, cath tract >5mm w/o mass, asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    2
    Hemorrhage enlargement, catheter tract > 5 mm with mass effect, asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Hemorrhage, new catheter tract <= 5 mm, asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 8 (37.50%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    2
    Hemorrhage, new catheter tract > 5 mm with mass effect, asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Hemorrhage, new catheter tract > 5 mm with mass effect, symptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Herniation, Brain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Hydrocephalus, Obstructive
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Hydrocephalus, communicating
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    3
    ICH hemorrhage enlargement, asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    ICH hemorrhage, new asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    ICH hemorrhage, new symptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    IVH hemorrhage enlargement - asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    4
    Increased midline shift
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Intracranial hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    2 / 36 (5.56%)
         occurrences all number
    5
    2
    4
    Peri-hemorrhagic ischemic change
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    SAH Hemorrhage, new asymptomatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Siezure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Ventriculitis, bacterial
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    4
    Ventriculitis, nonbacterial
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    8 / 36 (22.22%)
         occurrences all number
    0
    1
    9
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Bacteremia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    4
    Hyperglycemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    Hypokalemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    3
    Hyponatremia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    Hypoxemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Increased Blood Urea Nitrogen
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fever of unknown origin
         subjects affected / exposed
    3 / 8 (37.50%)
    4 / 8 (50.00%)
    8 / 36 (22.22%)
         occurrences all number
    3
    4
    8
    Respiratory, thoracic and mediastinal disorders
    Adult Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    1
    Aspiration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Atelectasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    3
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    9 / 36 (25.00%)
         occurrences all number
    1
    1
    9
    Pneumonia, aspiration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    0
    3
    Pulmonary edema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Tracheitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Ventilatory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute Renal Failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    4 / 36 (11.11%)
         occurrences all number
    1
    2
    4
    Infections and infestations
    Skin Exanthema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Edema (metabolic causes)
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2005
    Substantial Amendment The Notice of Acceptance was for the dose frequency phase of this study but at that time the dose finding stage had not been analysed. The dose finding phase has now been completed and a decision made about the dose level. For this phase the dose level will be 1.0mg. Following on from completion of the dose finding phase and from experience in that phase the project team at Johns Hopkins have made some amendments to the protocol. These were submitted to the appropriate ethical committee who requested further changes. These have all been incorporated in the attached documents. Documents enclosed include Notification of Amendment Form Updated Request for Authorisation Form Summary of changes from original Request for Authorisation Form Protocol Version 5.2 dated 24 October 2005 Summary of changes from protocol version 4.1 dated 15/03/2005 to protocol version 5.2 dated 24/10/2005.
    24 Aug 2006
    Substantial Amendment 2 The proposed number of patients in the first tier of the dose-frequency stage of this study has been recruited and the initial data have been analysed. A decision has been made by the Data and Safety Monitoring Board and the Steering Committee that more data are needed to further evaluate the 1.0mg q8hr dose. The current tier has therefore been expanded from 12 patients to 24. To date no patients have been recruited in the UK. The Protocol has not been amended and there are no changes to the information provided in the Request for Authorisation Form. However I enclose the following documents: Notification of Amendment Form Safety Report : Stage 2 Dose Tier 1 Results Letter from DSMB

    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/22382155
    http://www.ncbi.nlm.nih.gov/pubmed/21940973
    http://www.ncbi.nlm.nih.gov/pubmed/22474059
    http://www.ncbi.nlm.nih.gov/pubmed/23370203
    http://www.ncbi.nlm.nih.gov/pubmed/23463422
    http://www.ncbi.nlm.nih.gov/pubmed/26228884
    For support, Contact us.
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