• The primary outcome measure is 90-day status, categorized as favorable/unfavorable. A favorable outcome will be defined as NIHSS values of 0 or 1 at 90 days, while an unfavorable outcome will be defined as NIHSS of 2 or higher at 90 days post-stroke. [ Time Frame: 90 days ] [ Designated as safety issue: No ]
  

• Secondary outcome measures include 6-month post-stroke status and the following neuropsychological assessments: IQCODE-SF, GOS, mRS, BI, MMSE, RBANS, COWAT, BDI-II, NPI-Q, and Trail Making Tests A & B. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  

Drug: donepezil
Study participants will be treated with donepezil orally at an initial dose of 5 mg daily for the first 4 weeks, then increased at their 30-day visit by 5 mg to a maximum dose of 10 mg daily, if tolerated. If the participant does not tolerate the 10 mg dose, they will remain on 5 mg through the course of the study.

We hypothesize that donepezil (5 mg per day, titrated up to 10 mg per day as tolerated) will enhance recovery following stroke by improving attention, learning and memory thereby enhancing rehabilitation. Patients will be men and women with acute (< 24 hours of onset of symptoms) ischemic stroke. We will test this hypothesis in a Phase II trial that takes advantage of an existing National Institutes of Neurological Disorders and Stroke (NINDS) resource, the Phase III clinical trial of tPA for acute ischemic stroke, to establish whether a large efficacy study using donepezil is justified. The NINDS tPA stroke trial has been used as historical control data in pilot trials of reperfusion and neuroprotection. Our proposed trial has significance beyond the specific case of testing donepezil. It will create a novel scientific resource for testing other recovery-enhancing strategies by providing information on acute-to-chronic trajectories of cognition and instrumental activities of daily living (IADL) function following ischemic stroke.

Incorporating cognitive measures into the trial is in keeping with the Fifth Stroke Therapy Academic Industry Roundtable (STAIR V). Our study will use a stratified 2-stage Phase II design that, if successful, will help break the cost-innovation barrier by avoiding expensive Phase III trials with little chance of success.