Background: Donepezil has consistently been shown to be effective and well tolerated in the symptomatic treatment of Alzheimer's disease in placebo-controlled clinical trials. It has been shown to provide significant benefits in cognition, global function and activities of daily living in patients with mild-to-moderate Alzheimer's disease. However, in order to control for confounding factors, some clinical trials of donepezil have excluded patients with comorbid illness and concomitant medication use.
Objective: The objective of this study was to evaluate the efficacy, tolerability and safety of donepezil in a wider and more diverse sample of patients and centres than previous trials, reflecting routine clinical practice.
Methods: In this 12-week, open-label, multicentre trial, patients with probable mild-to-moderate Alzheimer's disease received donepezil 5 mg/day for 28 days, after which the dosage was increased to 10 mg/day according to the investigating clinician's judgement. Patients were enrolled at 246 study centres in 18 countries worldwide. Cognition was assessed by a trained clinician using the Mini-Mental State Examination (MMSE) at baseline, week 4 and week 12 (or last visit). Changes in patient activity and social interaction were evaluated using a caregiver diary. Each week, caregivers recorded their impression of change compared with baseline on three aspects of patient behaviour using a 5-point scale. Efficacy analyses were performed on the intent-to-treat population. Significance was determined using the paired t-test (0.05 significance level). Tolerability and safety were assessed by monitoring adverse events, physical examinations, vital signs, clinical laboratory test abnormalities and ECG findings throughout the study.
Results: A total of 1113 patients received donepezil (mean baseline MMSE score [+/-SD] 18.74 +/- 5.21). 989 (88.9%) patients completed the study; 59 (5%) patients discontinued because of adverse events. Most patients were taking at least one concomitant medication (n = 802; 72%) and had at least one comorbid medical condition (n = 745; 67%) on study entry. Donepezil significantly improved cognition compared with baseline at weeks 4 and 12, and at week 12 using a last observation carried forward (LOCF) analysis (all p < 0.0001). Mean change from baseline MMSE score (+/-SE) at week 12-LOCF was +1.73 +/- 0.10. Donepezil was also associated with significant improvements in patient social interaction, engagement and interest, and initiation of pleasurable activities at all weekly assessments and week 12-LOCF (all p < 0.0001). Donepezil was generally well tolerated; adverse events were consistent with the known safety profile of donepezil.
Conclusion: Donepezil treatment resulted in statistically significant improvements in cognition and patient activity and social behaviour, and was generally well tolerated despite high levels of comorbid illness and concomitant medication use. The results of this open-label study in a large patient population are consistent with those from controlled trials and support that donepezil is effective in the treatment of mild-to-moderate Alzheimer's disease in everyday practice.