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Rachelle S. Doody, MD, PhD; David S. Geldmacher, MD; Barry Gordon, MD, PhD; Carlos A. Perdomo, MS; Raymond D. Pratt, PhD; for the Donepezil Study Group

Arch Neurol. 2001;58:427-433.

Background  Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function.

Objective  To investigate the long-term benefits of donepezil treatment in patients with AD.

Design  Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout).

Interventions  All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged.

Measures  Primary efficacy measures were the Alzheimer's Disease Assessment Scale–cognitive subscale and the Clinical Dementia Rating–Sum of the Boxes.

Results  After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale–cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events.

Conclusions  Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

From the Department of Neurology, Baylor College of Medicine, Houston, Tex (Dr Doody); University Hospitals of Cleveland and the Department of Neurology, Case Western Reserve University, Cleveland, Ohio (Dr Geldmacher); the Departments of Neurology and Cognitive Science, Johns Hopkins University School of Medicine, Baltimore, Md (Dr Gordon); and Biometrics (Mr Perdomo) and Clinical Research (Dr Pratt), Eisai Inc, Teaneck, NJ. A complete list of the Donepezil Study Group investigators appears on page 429. Dr Doody has received research support, consulting fees, and honoraria from Eisai Inc and Pfizer. Dr Geldmacher has received consulting fees and honoraria from Eisai Inc and research support, consulting fees, and honoraria from Pfizer, and he holds minority stock interest in Pfizer. Dr Gordon has received research support, consulting fees, and speaker fees from Eisai Inc and Pfizer. Drs Perdomo and Pratt are full-time employess of Eisai Inc.

Corresponding author and reprints: Rachelle S. Doody, MD, PhD, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030-3498.

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