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    Clinical Trial Results:
    Influence of intra-arterial cerebral Papaverine Hydrochloride on cerebral glucose, lactate, pyruvate, glycerol, and glutamate concentrations, cerebral oxygenation, angiographic vasospasm, delayed stroke rates, and neurologic outcome in patients suffering life-threatening post-subarachnoid hemorrhage cerebral vasospasm irresponsive to hyperdynamic treatment.

    Summary
    EudraCT number
    		 2010-023878-40
    Trial protocol
    		 AT  
    Global end of trial date
    10 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Feb 2020
    First version publication date
    19 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2.3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria,
    Public contact
    Neurosurgery, AKH Wien, Medical University Vienna, 0043 1404002565,
    Scientific contact
    Neurosurgery, AKH Wien, Medical University Vienna, 0043 1404002565,
    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
    21 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    o demonstrate the influence of intra-arterial cerebral Papaverine Hydrochloride on cerebral glucose, lactate, pyruvate, glycerol, and glutamate concentrations and cerebral oxygenation in patients suffering severe post-SAH cerebral VSP
    Protection of trial subjects
    Continuous multimodality Neuromonitoring including intracranial pressure, brain tissue oxygen tension and cerebral microdialysis monitoring Computed tomography scans Daily blood tests
    Background therapy
    		 sedation: propofol and remifentanil, switched to midazolam (up to 20 mg/h) and sufentanil (up to 0.25 µg/kg/min) after 3 to 5 days. Ketamine (up to 200mg/h), and metohexital (up to 1mg/kg/h) was added in case of inadequate sedation. Nimodpine: orally, 60 mg every 4 hours
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient recruitment was performed between May 2016 and March 2019. Patients fulfilling the inclusion criteria (multimodality monitoring and clinical indication for intra-arterial papaverine-hydrochloride administration) were recruited consecutively.

    Pre-assignment
    Screening details
    		 Screening visit included: physical and neurological examination, vital signs, laboratory tests (haematology, chemistry, serology), transcranial doppler ultrasound, medical and medication history, concomitant medication

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 intra-arterial Papaverine-Hydrochloride
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Papaverin-Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    super-selective intra-arterial administration of 75 - 125 mg (concentration 5 mg/mL) in each spastic vascular territory manually via microcatheter

    Number of subjects in period 1
    		intra-arterial Papaverine-Hydrochloride
    Started
    10
    Completed
    10
    Period 2
    Period 2 title
    12 hours post-interventional
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 intra-arterial Papaverine-Hydrochloride
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Papaverin-Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    super-selective intra-arterial administration of 75 - 125 mg (concentration 5 mg/mL) in each spastic vascular territory manually via microcatheter

    Number of subjects in period 2
    		intra-arterial Papaverine-Hydrochloride
    Started
    10
    Completed
    10
    Period 3
    Period 3 title
    7 days post intervention
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 intra-arterial Papaverine-Hydrochloride
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Papaverin-Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    super-selective intra-arterial administration of 75 - 125 mg (concentration 5 mg/mL) in each spastic vascular territory manually via microcatheter

    Number of subjects in period 3
    		intra-arterial Papaverine-Hydrochloride
    Started
    10
    Completed
    10
    Period 4
    Period 4 title
    3 month functional outcome
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 intra-arterial Papaverine-Hydrochloride
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Papaverin-Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    super-selective intra-arterial administration of 75 - 125 mg (concentration 5 mg/mL) in each spastic vascular territory manually via microcatheter

    Number of subjects in period 4
    		intra-arterial Papaverine-Hydrochloride
    Started
    10
    Completed
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 10 10
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 51 (44 to 55) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 2 2
    Subject analysis sets

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All included patients

    Subject analysis sets values
    		 All patients
    Number of subjects
    10
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    10
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    51 (44 to 55)
    Gender categorical
    Units: Subjects
        Female
    8
        Male
    2

    End points

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    End points reporting groups
    Reporting group title
    intra-arterial Papaverine-Hydrochloride
    Reporting group description
    		 -
    Reporting group title
    intra-arterial Papaverine-Hydrochloride
    Reporting group description
    		 -
    Reporting group title
    intra-arterial Papaverine-Hydrochloride
    Reporting group description
    		 -
    Reporting group title
    intra-arterial Papaverine-Hydrochloride
    Reporting group description
    		 -

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All included patients

    Primary: Cerebral lactate concentration following intra-arterial Papaverine-Hydrochloride administration

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    End point title
    		 Cerebral lactate concentration following intra-arterial Papaverine-Hydrochloride administration
    End point description
    End point type
    Primary
    End point timeframe
    within 12 hours after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.8 ± 1.4
    5.1 ± 2.1
    Statistical analysis title
    		 comparison to baseline
    Comparison groups
    intra-arterial Papaverine-Hydrochloride v intra-arterial Papaverine-Hydrochloride
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - single-arm: comparison of baseline with post-interventional values

    Primary: Cerebral lactate-pyruvate ratio concentration following intra-arterial Papaverine-Hydrochloride administration

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    End point title
    		 Cerebral lactate-pyruvate ratio concentration following intra-arterial Papaverine-Hydrochloride administration
    End point description
    End point type
    Primary
    End point timeframe
    within 12 hours after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: no units (ratio)
        arithmetic mean (standard deviation)
    39.3 ± 15.3
    30.5 ± 6.7
    Statistical analysis title
    		 comparison to baseline
    Comparison groups
    intra-arterial Papaverine-Hydrochloride v intra-arterial Papaverine-Hydrochloride
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - single-arm: comparison of baseline with post-interventional values

    Primary: Cerebral glycerol concentration following intra-arterial Papaverine-Hydrochloride administration

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    End point title
    		 Cerebral glycerol concentration following intra-arterial Papaverine-Hydrochloride administration
    End point description
    End point type
    Primary
    End point timeframe
    within 12 hours after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: µmol/L
        arithmetic mean (standard deviation)
    92.8 ± 86.7
    104.4 ± 89.8
    Statistical analysis title
    		 comparison to baseline
    Comparison groups
    intra-arterial Papaverine-Hydrochloride v intra-arterial Papaverine-Hydrochloride
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - single-arm: comparison of baseline with post-interventional values

    Primary: Cerebral glutamate concentration following intra-arterial Papaverine-Hydrochloride administration

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    End point title
    		 Cerebral glutamate concentration following intra-arterial Papaverine-Hydrochloride administration
    End point description
    End point type
    Primary
    End point timeframe
    within 12 hours after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: µmol/L
        arithmetic mean (standard deviation)
    10.7 ± 16.3
    6.6 ± 8.9
    Statistical analysis title
    		 comparison to baseline
    Comparison groups
    intra-arterial Papaverine-Hydrochloride v intra-arterial Papaverine-Hydrochloride
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - single-arm: comparison of baseline with post-interventional values

    Primary: Cerebral oxygenation concentration following intra-arterial Papaverine-Hydrochloride administration

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    End point title
    		 Cerebral oxygenation concentration following intra-arterial Papaverine-Hydrochloride administration
    End point description
    End point type
    Primary
    End point timeframe
    within 12 hours after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: mmHg
        arithmetic mean (standard deviation)
    20.8 ± 12.4
    23.7 ± 12.5
    Statistical analysis title
    		 comparison to baseline
    Comparison groups
    intra-arterial Papaverine-Hydrochloride v intra-arterial Papaverine-Hydrochloride
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - single-arm: comparison of baseline with post-interventional values

    Secondary: Improvement of angiographic vasospasm

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    End point title
    		 Improvement of angiographic vasospasm
    End point description
    End point type
    Secondary
    End point timeframe
    during angiography directly after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: number
    0
    8
    No statistical analyses for this end point

    Secondary: Incidence of delayed ischemic strokes

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    End point title
    		 Incidence of delayed ischemic strokes
    End point description
    End point type
    Secondary
    End point timeframe
    within 7 days following the endovascular intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    10
    Units: numbers
    0
    5
    No statistical analyses for this end point

    Secondary: Functional Outcome after 3 month

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    End point title
    		 Functional Outcome after 3 month
    End point description
    modified Rankin scale
    End point type
    Secondary
    End point timeframe
    3 month after intervention
    End point values
    		 intra-arterial Papaverine-Hydrochloride
    Number of subjects analysed
    10
    Units: Points
        median (inter-quartile range (Q1-Q3))
    4 (1 to 5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 month after intra-arterial Papaverine-Hydrochloride administration
    Adverse event reporting additional description
    regular investigator assessment and laboratories testing
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    intra-arterial Papaverine-Hydrochloride
    Reporting group description
    		 -

    Serious adverse events
    		 intra-arterial Papaverine-Hydrochloride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Nervous system disorders
    Death
    Additional description: Death due to multiple cerebral infarction with brain herniation
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebral infarction
    Additional description: new cerebral infarction due to underlying disease (severe post-subarachnoid haemorrhage vasospasm)
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 intra-arterial Papaverine-Hydrochloride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    Nervous system disorders
    Intracranial pressure increased
         subjects affected / exposed
    10 / 10 (100.00%)
         occurrences all number
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    early termination leading to a small number of subjects analysed

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31792510
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