Enhancing Recovery After Acute Ischemic Stroke with Donepezil as an Adjuvant Therapy to Standard Medical Care: Results of a Phase IIa Clinical Trial

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 pre-specified 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.