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A Randomized Placebo-Controlled Trial

Ben Seltzer, MD; Parvaneh Zolnouni, MD; Margarita Nunez, MD; Robert Goldman, PhD; Dinesh Kumar, MA; John Ieni, PhD; Sharon Richardson, PhD; for the Donepezil "402" Study Group

Arch Neurol. 2004;61:1852-1856.

Objective  To evaluate the efficacy of donepezil in patients with early-stage Alzheimer disease.

Design  Multicenter, randomized, double-blind, 24-week, placebo-controlled study that enrolled patients with early-stage Alzheimer disease. Patients were randomized in an approximately 2:1 ratio to donepezil, 5 mg/d, for the first 6 weeks, with a forced escalation to 10 mg/d thereafter (n = 96), or placebo (n = 57). The primary efficacy measure was the modified Alzheimer Disease Assessment Scale–cognitive subscale. Secondary efficacy measures included the Mini-Mental State Examination, the Computerized Memory Battery Test, the Clinical Dementia Rating Scale–Sum of the Boxes, the Patient Global Assessment Scale, and the Apathy Scale.

Results  Improvements favoring donepezil on the Alzheimer Disease Assessment Scale–cognitive subscale were found at weeks 12 and 24 and at the end point (last observation carried forward); treatment differences were 1.9 (P = .03), 2.3 (P = .008), and 2.3 (P = .001) points, respectively. Improvements favoring donepezil on the Mini-Mental State Examination were found at weeks 6, 12, and 24 and at the end point (last observation carried forward); treatment differences were 1.4 (P = .02), 1.2 (P = .04), 1.4 (P = .03), and 1.8 (P = .002) points, respectively. Donepezil-treated patients showed greater mean improvement compared with placebo-treated patients on the following Computerized Memory Battery Test subscales: facial recognition (P = .007 in the intent-to-treat population and P = .04 in the fully evaluable population), first and last name total acquisition (P = .02), and name-face association delayed recall (P = .04). Donepezil was safe and well tolerated in this population; serious adverse events occurred in similar numbers of donepezil- and placebo-treated patients.

Conclusion  These data suggest significant treatment benefits of donepezil in early-stage Alzheimer disease, supporting the initiation of therapy early in the disease course to improve daily cognitive functioning.

Author Affiliations: Department of Psychiatry and Neurology, Tulane University School of Medicine, New Orleans, La (Dr Seltzer); California Clinical Trials Medical Group, Beverly Hills (Dr Zolnouni); ICSL Clinical Studies, St Petersburg, Fla (Dr Nunez); Pfizer Inc, New York, NY (Dr Goldman); and Eisai Inc, Teaneck, NJ (Mr Kumar and Drs Ieni and Richardson).

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