Objective: A double-blind trial has demonstrated donepezil’s benefits in moderate to severe Alzheimer’s disease (AD) patients (sMMSE scores 5-17; Feldman et al. Neurology 2001). The current analysis focuses on the subgroup of patients with severe AD.
Design: 290 patients (sMMSE score 5-17) were divided at the median baseline sMMSE score (12); 145 patients were classified as having severe AD (sMMSE score 5-12).
Methods: Patients received donepezil (5 mg/day for 28 days,10 mg/day thereafter per clinician’s judgment, n=72), or placebo for 24 weeks (n=73). Patients were assessed at Weeks 4, 8, 12, 18 and 24. The primary outcome measure was the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC-plus) at Week 24, using a LOCF analysis.
Results: Baseline patient demographics were similar between treatment groups. Mean baseline sMMSE scores (± SD) were 9.0 ± 2.19 for the donepezil group and 8.9 ± 2.19 for the placebo group. Mean CIBIC-plus scores for donepezil-treated patients showed improvement or minimal change from baseline throughout the study; mean scores for the placebo group showed a steady decline. Treatment differences were significant in favor of donepezil at each assessment and Week 24 LOCF (mean difference = 0.7; P=0.0002). Mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group were improved from baseline throughout the study, and were significantly different from placebo at each assessment and Week 24 LOCF (mean difference = 2.0 for sMMSE; P=0.0022, and 7.4 for SIB; P=0.0017). Donepezi patients showed significantly less decline than placebo-treated patients on the Disability Assessment for Dementia at each assessment and at Week 24 LOCF (mean difference = 7.2; P=0.0082). Mean change from baseline scores on the Neuropsychiatric Inventory (NPI) 12-item total improved throughout the study for donepezil patients and were significantly different from placebo at Weeks 4, 18, 24 and Week 24 LOCF (mean difference = 6.9; P=0.0062). Benefits in 11/12 NPI items were observed with donepezil, compared with placebo at Week 24 LOCF, with significant differences for depression, anxiety and apathy (P<0.05). For 8 NPI items more donepezil patients showed a reduction in baseline symptoms (depression and anxiety, P<0.05). 90% of donepezil- and 86% of placebo-treated patients completed the trial, with 7% and 5%, respectively, discontinuing due to adverse events. 82% of donepezil- and 78% of placebo-treated patients experienced adverse events, the majority of which were rated as mild or moderately severe.
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