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    Clinical Trial Results:
    An open label randomised controlled trial investigating the effect of donepezil on regional cerebral blood flow in adults with aneurysmal subarachnoid haemorrhage.

    Summary
    EudraCT number
    		 2013-002457-30
    Trial protocol
    		 GB  
    Global end of trial date
    10 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2019
    First version publication date
    02 Dec 2019
    Other versions
    Summary report(s)
    		 End of Trial Form

    Trial information

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    Trial identification
    Sponsor protocol code
    13.0099
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St Georges University of London
    Sponsor organisation address
    Cranmer Terrace, London, United Kingdom, SW17 0QT
    Public contact
    Dr Jeremy B Madigan, St George's Univeristy of London, 0044 02087254481, jeremy.madigan@nhs.net
    Scientific contact
    Dr Jeremy B Madigan, St George's Univeristy of London, 0044 02087254481, jeremy.madigan@nhs.net
    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
    10 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To measure the effects of donepezil on regional cerebral blood flow following aneurysmal subarachnoid haemorrhage Secondary objectives To assess whether the administration of donepezil to study participants with acute SAH: I. Is safe. II. Is tolerable for 21 days.
    Protection of trial subjects
    The data monitoring committee will review the following trial data after the enrolment of the first 10 participants, and for every 20 participants in the trial after that.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    13
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Clinical history and examination as part of routine care, including medication and allergy history. Plain CT head and CT Angiogram. Bloods: Urea & electrolytes, liver function tests. Pregnancy test for potential female participants with child-bearing potential.

    Pre-assignment period milestones
    Number of subjects started
    		 19
    Number of subjects completed
    		 19

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Donepezil
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Donepezil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    To those randomised to the donepezil arm, the first dose will be a loading dose of 20mg donepezil in suspension given via nasogastric tube under general anaesthesia. Subsequent doses will be 5mg donepezil once daily given orally by either dissolving or dispersing on the tongue or administered via a nasogastric tube, depending on the conscious level and safety of swallow for each participant. Doses should be taken at the same time each day preferably in the evening. All trial participants will receive donepezil for a total of 21 days, to cover the vasospasm ‘at risk’ period.

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Donepezil Control
    Started
    10
    9
    Overall trial
    9
    9
    Completed
    9
    9
    Not completed
    1
    0
         Adverse event, serious fatal
    1
    -

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 8 8

    End points

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    End points reporting groups
    Reporting group title
    Donepezil
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Primary: Mean cerebral blood flow (mL/100g/min

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    End point title
    		 Mean cerebral blood flow (mL/100g/min [1] [2]
    End point description
    Xenon CT Perfusion scans
    End point type
    Primary
    End point timeframe
    At least 3 hours following the first 20mg loading dose of Donepezil
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis was not reported due to low number of recruited patients.
    [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: The analysis was not reported due to low number of recruited patients.
    End point values
    		 Donepezil
    Number of subjects analysed
    8
    Units: mL/100g/min
        number (not applicable)
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    To report Serious Adverse Events to Sponsor within 24 hours of notification. All Adverse Events to be recorded on Adverse Event log.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: See adverse events attached.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2013
    Concerns were raised by the REC about the safety of the single 20mg Donepezil dose, the protocol has been amended such that an interim analysis will be performed by a data monitoring committee after enrolment of the first 10 participants. This will be to investigate the occurrence of defined adverse events in relation to donepezil administration.
    09 Apr 2014
    Addition of Exclusion criteria 5.2 for requirement of FiO2 > 0.6 within protocol Additional section within protocol added 8.7.2.1 ‘technical criteria for participant replacement’ Additional section added within protocol 8.7.2.2 ‘ Clinical criteria for participant replacement’
    12 Dec 2014
    Removal of CT angiogram performed following aneurysm coiling
    22 Sep 2015
    Temporary Halt

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Nov 2016
    The trial centre has installed a new CT scanner which is not compatible with the Xenon analysis software (despite reassurances from the CT manufacturer to the contrary). It is not possible to recruit any further subjects as we can no longer acquire primary endpoint data.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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