Effects of Donepezil on Regional Cerebral Blood Flow Following Aneurysmal Subarachnoid Haemorrhage

NCT02222727 | Terminated Phase 2

• 2 other identifiers: 13.00992013-002457-30
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Aneurysmal Subarachnoid Hemorrhage; Delayed Neurological Deficit; Delayed Cerebral Ischemia; Vasospasm

Outcome Measures

Primary Outcomes (1)

• Cerebral blood flow

  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.

  Within 3-4 hours of receiving drug

Secondary Outcomes (2)

• Number of participants with adverse events.

  6 weeks from enrolment

• Disability assessment

  6 months from enrolment

Study Arms (2)

Donepezil

ACTIVE COMPARATOR

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.

Drug: Donepezil

Control

NO INTERVENTION

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.

Interventions

Donepezil DRUG

Loading 20 mg dose of donepezil on first day of recruitment followed by once daily 5 mg dose for subsequent twenty days

Also known as: Aricept

Donepezil

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age 18 - 85 years
• Fisher score 2-4
• recruitment within 12 - 72 hours of hemorrhage

You may not qualify if:

• pregnancy
• breast feeding
• allergy to donepezil or other piperidine derivatives
• participants unwilling to use appropriate birth control up to 6 weeks after enrolment
• known dementia
• severe liver failure (Child-Pugh C)
• sick sinus syndrome or other supraventricular cardiac conduction abnormalities
• inspired oxygen requirement greater than 60%
• history of brittle asthma or obstructive airway disease
• aneurysm unsuitable for endovascular coiling
• concomitant use of cholinesterase inhibitor (e.g. rivastigmine, galantamine, etc)

Sponsors & Collaborators

• St George's, University of London: lead

Study Sites (1)

St George's University of London

London, SW17 0RE, United Kingdom

Location

MeSH Terms

Conditions

Subarachnoid Hemorrhage

Interventions

Donepezil

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds

Study Officials

• Jeremy Madigan, FRCR

  St George's Hospital NHS Trust

  STUDY DIRECTOR

• Ramanan Sivakumaran, MRCS

  St George's, University of London

  PRINCIPAL INVESTIGATOR

• Marios Papadopouos, MD FRCS(SN)

  St George's, University of London

  PRINCIPAL INVESTIGATOR

• Kunle Mduaoi

  St George's, University of London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2014
• First Posted: August 21, 2014
• Study Start: January 1, 2014
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: September 11, 2017

Record last verified: 2017-09

Locations

GB (1)