Objective: To examine the domains influencing physicians’ judgment of clinical benefit in Alzheimer’s disease (AD) patients, during the pre-randomization phase of the donepezil AWARE (Aricept WAshout and REchallenge) study.
Background: AD patients who do not exhibit improvement are often discontinued from cholinesterase inhibitor therapy. However, although therapeutic benefits may be apparent in several domains, such as cognition, behavior, and activities of daily living (ADL), there is currently no standard clinical approach to determine treatment success in AD patients.
Design: AWARE consists of 3 phases: 1) 24-week, pre-randomization, open-label donepezil treatment phase; 2) 12-week, randomized, double-blind, placebo-controlled phase; 3) 12-week, single-blind donepezil treatment phase. During the first, open-label phase, all patients received donepezil. During the subsequent, double-blind phase, patients were randomized to continue on donepezil treatment or switch to placebo. In the final, single-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil. Results from the pre-randomization phase are presented here.
Materials and Methods: Patients with mild to moderate AD received donepezil (10 mg/day) for 12-24 weeks. Clinical benefit was assessed at Weeks 12, 18, and 24. Patients who exhibited improvement from baseline on the Mini-Mental State Examination (MMSE) or whose physician was sufficiently certain of clinical benefit to warrant continued treatment (assessed by formal questionnaire) were rated as showing "observed clinical benefit". Physicians indicated which domains (cognition, ADL, behavior, caregiver request, other) most influenced their decision. Patients showing “no apparent clinical benefit” were randomized to continue in the second, double-blind phase of AWARE.
Results: Clinical benefit was classified in 619 of the 817 enrolled patients. The majority (70%) of physicians’ decisions were based upon cognition, whereas other domains were less influential (behavior, 14%; ADL, 10%; caregiver request, 5%; other, 1%). 426 patients showed “observed clinical benefit” (MMSE mean change from baseline, 2.4), and physicians were sufficiently certain of benefit to warrant continued therapy in 400 of these.
Conclusion: Cognition was the most influential domain in the majority of physicians’ decisions regarding clinical benefit. Strong agreement between physician global rating of the patient and the MMSE supports this observation.
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