Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: results of a phase IIA clinical trial.

Author(s): Barrett KM, Brott TG, Brown RD Jr, Carter RE, Geske JR, Graff-Radford NR, McNeil RB, Meschia JF

Affiliation(s): Department of Neurology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.

Publication date & source: 2011-05, J Stroke Cerebrovasc Dis., 20(3):177-82. Epub 2011 Feb 3.

Publication type: Clinical Trial, Phase II; Multicenter Study; Research Support, Non-U.S. Gov't

BACKGROUND: Our aim was to assess the safety, tolerability, and efficacy signal of early donepezil administration with regard to enhancing recovery in a diverse acute ischemic stroke population. METHODS: This was a multicenter, single-arm, National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator trial-controlled, modified 2-stage adaptive clinical trial set in 2 tertiary care hospitals in the United States. Adults with ischemic stroke treated within 24 hours after onset of symptoms were included. The intervention studied was donepezil 5 mg/day for 30 days, followed by an increase to 10 mg/day for 60 days. Our main outcome measures included treatment-related adverse events and side effects. The primary favorable outcome was a 90-day National Institutes of Health Stroke Scale (NIHSS) score </=1. Neurologic, cognitive, functional, and psychological outcomes were assessed longitudinally. RESULTS: Thirty-three adults (median age 66 years; 59% female; 39% received tissue plasminogen activator) initiated treatment with donepezil. There were no treatment-related serious adverse events. Three participants (9%) discontinued donepezil because of side effects and 3 participants (9%) required a reduction to 5 mg/day after titration to 10 mg/day. Fifteen participants (45%) had a favorable outcome (NIHSS score </=1 at day 90), and the study met prespecified criteria for continuing to a randomized trial (P < .10). Statistically significant improvements from baseline were observed with several secondary cognitive measures, including the Trail Making Tests and Mini-Mental State Exam (P < .01 for both). CONCLUSIONS: Adjuvant donepezil therapy initiated within 24 hours of acute ischemic stroke was safe and tolerated at 5 mg/day to 10 mg/day. The study met a priori criteria to move forward with a randomized clinical trial. Copyright (c) 2011 National Stroke Association. Published by Elsevier Inc. All rights reserved.