title: Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: results of a phase IIA clinical trial.
abstract: 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.
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Barrett
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Brott
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brown
authors.forename: Rickey E
authors.initials: RE
authors.lastname: Carter
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Geske
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: McNeil
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D003071:Cognition / Q000187:drug effects; D004185:Disability Evaluation; D000077265:Donepezil; D004334:Drug Administration Schedule; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D005431:Florida; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D020127:Recovery of Function; D012720:Severity of Illness Index; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D005343:Fibrinolytic Agents; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D010959:Tissue Plasminogen Activator