<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02222727</url>
  </required_header>
  <id_info>
    <org_study_id>13.0099</org_study_id>
    <secondary_id>2013-002457-30</secondary_id>
    <nct_id>NCT02222727</nct_id>
  </id_info>
  <brief_title>Effects of Donepezil on Regional Cerebral Blood Flow Following Aneurysmal Subarachnoid Haemorrhage</brief_title>
  <acronym>DASH</acronym>
  <official_title>Effects of Donepezil on Regional Cerebral Blood Flow Following Aneurysmal Subarachnoid Haemorrhage</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St George's, University of London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St George's, University of London</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Introduction&#xD;
&#xD;
      Aneurysmal subarachnoid hemorrhage (aSAH) is bleeding around the under surface of the brain&#xD;
      caused by rupture of an aneurysm arising from a blood vessel. Stroke may occur in&#xD;
      approximately one third of patients as a result of narrowing of the blood vessels around the&#xD;
      brain, following aSAH.&#xD;
&#xD;
      One theory as to why this may happen is because bleeding around the base of the brain damages&#xD;
      particular cells (neurons) that control blood flow around the rest of the brain. These&#xD;
      neurons may control blood flow by releasing a neurotransmitter called Acetyl Choline (ACh).&#xD;
      Our hypothesis is that damage to these neurons may prevent the production of ACh, which then&#xD;
      causes reduced blood flow and stroke if left untreated.&#xD;
&#xD;
      By stimulating these neurons, we aim to investigate whether it is possible to improve the&#xD;
      blood flow around brain and ultimately prevent strokes in patients following subarachnoid&#xD;
      haemorrhage. Donepezil, a drug widely used in dementia, inhibits the brain's natural break&#xD;
      down of ACh. We predict that by increasing the amount of Ach in these neurons, donepezil may&#xD;
      improve blood flow to the brain, reducing the chance of developing stroke.&#xD;
&#xD;
      Trial Protocol&#xD;
&#xD;
      All patients admitted to St George's hospital with a confirmed aneurysmal subarachnoid&#xD;
      haemorrhage between the ages of 18 and 85 years old will be invited to participate in the&#xD;
      trial. The protocol has been designed to take place around the patients' aneurysm treatment,&#xD;
      which is performed under general anesthesia (GA). Recruited participants will be anesthetized&#xD;
      for their aneurysm treatment and then enter the study.&#xD;
&#xD;
      All trial participants will have a Xenon CT scan under GA to assess brain blood flow prior to&#xD;
      having treatment of their aneurysm. Patients randomized to donepezil treatment will receive a&#xD;
      loading dose of 20mg via a feeding tube immediately after their Xenon scan. Patients in the&#xD;
      control group will not receive the drug.&#xD;
&#xD;
      All patients in the trial will undergo repeat Xenon perfusion scanning under GA between 3 and&#xD;
      4 hours after their first scan, which coincides with the completion of their aneurysm&#xD;
      treatment. Those in the donepezil group will then receive a daily dose of 5 mg for a period&#xD;
      of 21 days.&#xD;
&#xD;
      All aspects of care other than those related to the trial will be the same as for any other&#xD;
      subarachnoid haemorrhage patients. Patients (or their legal representative for those unable&#xD;
      to consent) will be able to decline participation in the trial or withdraw at any point.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    CT scanner software incompatible&#xD;
  </why_stopped>
  <start_date>January 2014</start_date>
  <completion_date type="Actual">November 2016</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cerebral blood flow</measure>
    <time_frame>Within 3-4 hours of receiving drug</time_frame>
    <description>Baseline xenon perfusion CT (XeCTP) scan performed immediately before donepezil loading dose administered. Follow-up XeCTP scan minimum of 3 hours after loading dose.&#xD;
For control group patients, baseline XeCTP scan performed before aneurysm treatment and follow-up scan 3-4 hours after first scan.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events.</measure>
    <time_frame>6 weeks from enrolment</time_frame>
    <description>Participants receiving donepezil will continue to take for 21 days in total and the washout period for the drug is approximately 2 weeks accounting for a total evaluation period of 5-6 weeks.&#xD;
All participants will be regularly evaluated by clinical staff while inpatients under care of the neurosurgical service. Those discharged prior to the 6 week period will be followed up regularly by telephone and provided with a diary to record potential adverse events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disability assessment</measure>
    <time_frame>6 months from enrolment</time_frame>
    <description>All participants will have a modified Rankin Score (mRS) at 6 months to assess their level of disability in comparison with their status on enrolment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Aneurysmal Subarachnoid Hemorrhage</condition>
  <condition>Delayed Neurological Deficit</condition>
  <condition>Delayed Cerebral Ischemia</condition>
  <condition>Vasospasm</condition>
  <arm_group>
    <arm_group_label>Donepezil</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants in the donepezil arm will receive the drug for 21 days as specified in the protocol in addition to current best medical treatment for aSAH patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Control group participants will not receive a placebo drug but will undergo cerebral blood flow imaging in the same manner as the donepezil patients. All other aspects of treatment will be identical to that of aSAH patients not involved in the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Donepezil</intervention_name>
    <description>Loading 20 mg dose of donepezil on first day of recruitment followed by once daily 5 mg dose for subsequent twenty days</description>
    <arm_group_label>Donepezil</arm_group_label>
    <other_name>Aricept</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age 18 - 85 years&#xD;
&#xD;
          -  Fisher score 2-4&#xD;
&#xD;
          -  recruitment within 12 - 72 hours of hemorrhage&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  breast feeding&#xD;
&#xD;
          -  allergy to donepezil or other piperidine derivatives&#xD;
&#xD;
          -  participants unwilling to use appropriate birth control up to 6 weeks after enrolment&#xD;
&#xD;
          -  known dementia&#xD;
&#xD;
          -  severe liver failure (Child-Pugh C)&#xD;
&#xD;
          -  sick sinus syndrome or other supraventricular cardiac conduction abnormalities&#xD;
&#xD;
          -  inspired oxygen requirement greater than 60%&#xD;
&#xD;
          -  history of brittle asthma or obstructive airway disease&#xD;
&#xD;
          -  aneurysm unsuitable for endovascular coiling&#xD;
&#xD;
          -  concomitant use of cholinesterase inhibitor (e.g. rivastigmine, galantamine, etc)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeremy Madigan, FRCR</last_name>
    <role>Study Director</role>
    <affiliation>St George's Hospital NHS Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ramanan Sivakumaran, MRCS</last_name>
    <role>Principal Investigator</role>
    <affiliation>St George's, University of London</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marios Papadopouos, MD FRCS(SN)</last_name>
    <role>Principal Investigator</role>
    <affiliation>St George's, University of London</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kunle Mduaoi</last_name>
    <role>Principal Investigator</role>
    <affiliation>St George's, University of London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St George's University of London</name>
      <address>
        <city>London</city>
        <zip>SW17 0RE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>August 20, 2014</study_first_submitted>
  <study_first_submitted_qc>August 20, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 21, 2014</study_first_posted>
  <last_update_submitted>September 8, 2017</last_update_submitted>
  <last_update_submitted_qc>September 8, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Subarachnoid Hemorrhage</mesh_term>
    <mesh_term>Brain Ischemia</mesh_term>
    <mesh_term>Cerebral Infarction</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
    <mesh_term>Ischemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Donepezil</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02222727
org study id: 13.0099
secondary id: 2013-002457-30
nct id: NCT02222727
lead sponsor: 
has dmc: No
Introduction

      Aneurysmal subarachnoid hemorrhage (aSAH) is bleeding around the under surface of the brain
      caused by rupture of an aneurysm arising from a blood vessel. Stroke may occur in
      approximately one third of patients as a result of narrowing of the blood vessels around the
      brain, following aSAH.

      One theory as to why this may happen is because bleeding around the base of the brain damages
      particular cells (neurons) that control blood flow around the rest of the brain. These
      neurons may control blood flow by releasing a neurotransmitter called Acetyl Choline (ACh).
      Our hypothesis is that damage to these neurons may prevent the production of ACh, which then
      causes reduced blood flow and stroke if left untreated.

      By stimulating these neurons, we aim to investigate whether it is possible to improve the
      blood flow around brain and ultimately prevent strokes in patients following subarachnoid
      haemorrhage. Donepezil, a drug widely used in dementia, inhibits the brain's natural break
      down of ACh. We predict that by increasing the amount of Ach in these neurons, donepezil may
      improve blood flow to the brain, reducing the chance of developing stroke.

      Trial Protocol

      All patients admitted to St George's hospital with a confirmed aneurysmal subarachnoid
      haemorrhage between the ages of 18 and 85 years old will be invited to participate in the
      trial. The protocol has been designed to take place around the patients' aneurysm treatment,
      which is performed under general anesthesia (GA). Recruited participants will be anesthetized
      for their aneurysm treatment and then enter the study.

      All trial participants will have a Xenon CT scan under GA to assess brain blood flow prior to
      having treatment of their aneurysm. Patients randomized to donepezil treatment will receive a
      loading dose of 20mg via a feeding tube immediately after their Xenon scan. Patients in the
      control group will not receive the drug.

      All patients in the trial will undergo repeat Xenon perfusion scanning under GA between 3 and
      4 hours after their first scan, which coincides with the completion of their aneurysm
      treatment. Those in the donepezil group will then receive a daily dose of 5 mg for a period
      of 21 days.

      All aspects of care other than those related to the trial will be the same as for any other
      subarachnoid haemorrhage patients. Patients (or their legal representative for those unable
      to consent) will be able to decline participation in the trial or withdraw at any point.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cerebral blood flow
time frame: Within 3-4 hours of receiving drug
description: Baseline xenon perfusion CT (XeCTP) scan performed immediately before donepezil loading dose administered. Follow-up XeCTP scan minimum of 3 hours after loading dose.
For control group patients, baseline XeCTP scan performed before aneurysm treatment and follow-up scan 3-4 hours after first scan.
measure: Number of participants with adverse events.
time frame: 6 weeks from enrolment
description: Participants receiving donepezil will continue to take for 21 days in total and the washout period for the drug is approximately 2 weeks accounting for a total evaluation period of 5-6 weeks.
All participants will be regularly evaluated by clinical staff while inpatients under care of the neurosurgical service. Those discharged prior to the 6 week period will be followed up regularly by telephone and provided with a diary to record potential adverse events.
measure: Disability assessment
time frame: 6 months from enrolment
description: All participants will have a modified Rankin Score (mRS) at 6 months to assess their level of disability in comparison with their status on enrolment.
arm group label: Donepezil
arm group type: Active Comparator
description: Participants in the donepezil arm will receive the drug for 21 days as specified in the protocol in addition to current best medical treatment for aSAH patients.
arm group label: Control
arm group type: No Intervention
description: Control group participants will not receive a placebo drug but will undergo cerebral blood flow imaging in the same manner as the donepezil patients. All other aspects of treatment will be identical to that of aSAH patients not involved in the study.
intervention type: Drug
intervention name: Donepezil
description: Loading 20 mg dose of donepezil on first day of recruitment followed by once daily 5 mg dose for subsequent twenty days
arm group label: Donepezil
other name: Aricept
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Jeremy Madigan, FRCR
role: Study Director
affiliation: St George's Hospital NHS Trust
last name: Ramanan Sivakumaran, MRCS
role: Principal Investigator
affiliation: St George's, University of London
last name: Marios Papadopouos, MD FRCS(SN)
role: Principal Investigator
affiliation: St George's, University of London
last name: Kunle Mduaoi
role: Principal Investigator
affiliation: St George's, University of London
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Subarachnoid Hemorrhage
mesh term: Brain Ischemia
mesh term: Cerebral Infarction
mesh term: Hemorrhage
mesh term: Ischemia
mesh term: Donepezil