Effect of Donepezil on Cognition in Severe Alzheimer's Disease: A Pooled Data Analysis

Article type: Research Article

Authors: Cummings, Jeffrey^{a; *} | Jones, Roy^b | Wilkinson, David^c | Lopez, Oscar^d | Gauthier, Serge^e | Waldemar, Gunhild^f | Zhang, Richard^g | Xu, Yikang^g | Sun, Yijun^h | Richardson, Sharon^h | Mackell, Joan^g

Affiliations: [a] Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA | [b] RICE (Research Institute for the Care of Older People), Royal United Hospital, Bath, UK | [c] Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK | [d] Alzheimer's Disease Research Center, Departments of Neurology and Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA | [e] McGill Center for Studies in Aging, Douglas Mental Health University Institute, Douglas Hospital, Verdun, QC, Canada | [f] Memory Disorders Research Group, Department of Neurology; Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark | [g] Pfizer Global Pharmaceuticals, Pfizer Inc, New York, NY, USA | [h] Eisai Inc., Woodcliff Lake, NJ, USA

Correspondence: [*] Correspondence to: Jeffrey Cummings, Mary S. Easton Center for Alzheimer's Disease Research, 10911 Weyburn Avenue, Suite 200, Los Angeles, California 90068, USA. Tel.: +1 310 794 3665; Fax: +1 310 794 3148; E-mail: jcummings@mednet.ucla.edu.

Abstract: To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N = 904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1–5, 6–9, 10–12 and 13–17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6–9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17–0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

Keywords: Alzheimer's disease, cognition, donepezil, functional outcome, global outcome, placebo-controlled, pooled data analysis, severe Alzheimer's disease, Severe Impairment Battery

DOI: 10.3233/JAD-2010-100078

Journal: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 843-851, 2010