Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease

Background: Donepezil hydrochloride is a selective acetylcholinesterase inh ibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have d emonstrated 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 tr eatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a B-week placebo washout). Interventions: All patients (N=763) initially received donepezil, 5 mg/d, f or 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 ben efits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cog nitive subscale scores for patients who received 10 mg/d in the double-blin d study were evident compared with the other groups for 108 weeks of open-l abel treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline va lues for all patient groups. Although scores improved relative to the new o pen-label study baseline scores after drug use was restarted, patients rema ined below original baseline values. The most common adverse events were as sociated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse ev ents. Conclusions: Donepezil is an effective and safe drug for the long-term symp tomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.