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A Randomized Crossover Study

Steven M. Greenberg, MD, PhD; Marsha K. Tennis, RN; Laura B. Brown; Teresa Gomez-Isla, MD, PhD; Douglas L. Hayden, MA; David A. Schoenfeld, PhD; Katie L. Walsh; Claire Corwin, PA-C; Kirk R. Daffner, MD; Pamela Friedman; Mary-Ellen Meadows, PhD; Reisa A. Sperling, MD; John H. Growdon, MD

Arch Neurol. 2000;57:94-99.

Objective  To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice.

Design  Two-center, randomized, placebo-controlled, double-masked crossover study.

Setting  Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston.

Patients  Sixty individuals (30 men and 30 women; mean ± SD age, 75.0 ± 9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale.

Interventions  Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks.

Primary Outcome Measure  Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods.

Results  Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean ± SEM) 2.17 ± 0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E 4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each).

Conclusion  This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

From the Departments of Neurology, Partners HealthCare Inc of Massachusetts General Hospital (Drs Greenberg, Gomez-Isla, Schoenfeld, and Growdon, and Mss Tennis, Brown, and Walsh and Mr Hayden) and Brigham and Women's Hospital (Mss Corwin and Friedman and Drs Daffner, Meadows, and Sperling), Harvard Medical School, Boston, Mass.

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