Objective: The efficacy and tolerability of donepezil in patients with mild cognitive impairment (MCI) was evaluated in a 6-month, double-blind, placebo-controlled study.
Design: This was a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Materials and Methods: Enrolled patients had a global Clinical Dementia Rating of 0.5 and a Mini-Mental State Examination score ³24. Patients were randomized to receive placebo (n=137) or donepezil (n=132, 5 mg/d for 42 days and 10 mg/d thereafter). Efficacy measures included the Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of Change-Mild Cognitive Impairment scale (ADCS CGIC-MCI), modified Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), New York University (NYU) Paragraph test, Digit Span Backwards test, Symbol Digit Modalities test, and Patient Global Assessment (PGA). Least squares (LS) mean change from baseline at end point was determined for intent-to-treat (ITT) and fully evaluable (FE) populations. The FE population consisted of all patients who had a study medication compliance of at least 80% at the Week 24 visit and no significant protocol violations.
Results: In the evaluation of mean ADCS CGIC-MCI scores at endpoint, score distributions suggested a tendency for donepezil-treated subjects to show greater improvement from baseline than placebo-treated subjects, but differences were not statistically significant. Both treatment groups showed improvement in the NYU Paragraph Delayed Recall test. Mean change was consistently greater for donepezil-treated subjects than for placebo-treated subjects, and the difference was statistically significant for the FE population. Statistically significant differences favoring donepezil were seen for several secondary endpoints: the modified ADAS-cog total score, the WMS-R Digit Span Backwards test, the Symbol Digit Modalities test, and the PGA. Results favored donepezil, with trends towards significance, for several additional secondary endpoints, including the modified ADAS-cog Delayed Word Recall test, the ADCS CGIC-MCI cognition subdomain, the ADCS CGIC-MCI functional abilities subdomain, and the Number Cancellation test. Adverse events were reported by 88% of the donepezil group and 73% of the placebo group; most were mild or moderate in severity.
Conclusion: This is the first known placebo-controlled study of a cholinesterase inhibitor for the symptomatic treatment of MCI. Donepezil treatment significantly improved cognitive function relative to placebo in patients with amnestic MCI. These results suggest that donepezil is a safe and efficacious therapy in this patient population.
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