Objective: To assess the nature and extent of therapeutic benefits of continued donepezil treatment in Alzheimer’s disease (AD) patients judged as showing “no apparent clinical benefit” during initial treatment.
Background: AD patients who do not exhibit improvement are often discontinued from cholinesterase inhibitor therapy. However, as current methods of rating clinical benefit may be biased towards cognition, benefits in other domains might not be identified. Furthermore, due to the nature of disease progression in AD, patients who do not show improvement may still be experiencing therapeutic benefits.
Design: AWARE consists of 3 phases: 1) 24-week, pre-randomization, open-label donepezil treatment phase; 2) 12-week, randomized, double-blind, placebo-controlled treatment phase; 3) 12-week, single-blind donepezil treatment phase. During the open-label phase, all patients received donepezil 10 mg/day (5 mg/day for first 28 days then 10 mg/day thereafter). During the double-blind phase (presented here), selected patients were randomized to continue on donepezil treatment (10 mg/day) or switch to placebo.
Materials and Methods: Patients with mild to moderate AD (MMSE 10–26) received open-label donepezil for 12-24 weeks. Patients who exhibited decline or no change from baseline on the MMSE and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were rated as showing “no apparent clinical benefit” and randomized into the double-blind phase. Efficacy assessments during this phase included the MMSE, NPI, DAD, and ADAS-cog. Results for Week 12 intent-to-treat observed cases from the double-blind phase are reported, as least-squares mean change from baseline score.
Results: Of 817 enrolled patients, 202 were rated as “no apparent clinical benefit” and randomized to continue on donepezil (n=99) or switch to placebo (n=103). Significant differences in favor of the continuous donepezil group were observed on the MMSE (treatment difference -1.13, P=0.02) and the NPI (treatment difference 3.16, P=0.02). Donepezil-treated patients also showed less decline than placebo-treated patients on the DAD (treatment difference -3.67, P=0.11) and the ADAS-cog (treatment difference 0.57, P=0.53).
Conclusion: Although initially classified as showing “no apparent clinical benefit”, patients who continued to receive donepezil demonstrated significant cognitive and behavioral benefits compared with those who switched to placebo. Physicians should therefore be cautious when deciding whether to discontinue treatment in patients who apparently decline, as these patients may still experience significant treatment benefits.
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