Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial

Background There have been very limited investigations of cholinesterase inhibitor therapy in more advanced stages of Alzheimer's disease (AD). The efficacy and safety of donepezil were evaluated in post hoc analyses of a subgroup of patients with more severe AD (standardized Mini‐Mental State Examination [sMMSE] score 5–12) within a randomized, placebo‐controlled trial in moderate to severe AD (MSAD study). Additional analyses examined whether donepezil's treatment effects were consistent across the full range of baseline AD severity studied (sMMSE score 5–17). Methods Patients with moderate to severe AD (n = 290) who were living in the community or in assisted living facilities received donepezil or placebo for 24 weeks; n = 145 in the more severe AD subgroup. The primary outcome measure was the Clinician's Interview‐Based Impression of Change (CIBIC‐plus) with secondary outcomes including the sMMSE, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia. Analysis of Variance and Analysis of Covariance models tested for treatment×disease severity interaction in the full MSAD study sample. Results CIBIC‐plus scores for donepezil patients were significantly improved compared with placebo for each time‐point, with a 0.70 mean treatment difference at Week 24 last observation carried forward (LOCF; p = 0.0002). Significant differences favoring donepezil were noted at Week 24 LOCF for all secondary measures. There were no treatment×severity interactions for any of the efficacy measures. Conclusions In this analysis, donepezil had significant benefits over placebo on global, cognitive, functional, and behavioral measures in a subgroup of patients with more severe AD. Furthermore, the treatment effects of donepezil were not driven by a particular stratum within the moderate to severe dementia range. Copyright © 2005 John Wiley & Sons, Ltd.