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From the Karolinska Institutet, Alzheimer’s Disease Research Center, Division of Geriatric Medicine (Dr. Winblad), Huddinge Hospital B, Stockholm, Sweden; the Department of Geriatric Medicine (Dr. Engedal), Ullevaal University Hospital, Oslo, Norway; the Department of Neurology (Dr. Soininen), University and University Hospital of Kuopio, Kuopio, Finland; the Department of Psychiatry (Dr. Verhey), University Hospital of Maastricht, Institute of Brain and Behaviour, Maastricht, The Netherlands; The Neuroscience Center, Department of Neurology (Dr. Waldemar), Rigshospitalet, University Hospital, Copenhagen, Denmark; the Department of Family Medicine (Dr. Wimo), Umeå University, Umeå, Sweden; Pfizer AB (A.-L. Wetterholm and A. Haglund), Taby, Sweden; and Pfizer Pharmaceuticals Group (Drs. Zhang and Subbiah), Pfizer, Inc., New York, NY.
Address correspondence and reprint requests to Dr. Bengt Winblad, Karolinska Institutet, Alzheimer’s Disease Research Center, Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, Division of Geriatric Medicine, Huddinge Hospital B 84, 14186 Stockholm, Sweden; e-mail: Bengt.Winblad{at}neurotec.ki.se
Objective:— To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD.
Methods:— Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year.
Results:— The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Bråne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7% of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population.
Conclusion:— As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.
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