Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials

Abstract

Objective:

Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety.

Methods:

Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response.

Results:

Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2–3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups.

Conclusions:

These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.

Key words::

• Alzheimer's disease
• Behavior
• Clinical trials
• Cognition
• Donepezil
• Function
• Severe

Transparency

Declaration of funding

The reported analyses were performed and financed by Eisai Inc. and Pfizer Inc. All authors had full access to the data and participated in the preparation of the manuscript.

Declaration of financial/other relationships

B.W is a member of the speakers’ bureau/advisory board of Pfizer Inc and Eisai Inc. S.E.B. is the recipient of research grants from Eisai Inc, Pfizer Inc, Myriad Pharmaceuticals, Novartis Pharmaceuticals Corporation, Roche, and Senexa, and is the recipient of honoraria and speakers’ fees from Pfizer Inc, Novartis Pharmaceuticals Corporation, H. Lundbeck A/S, Ortho-McNeill-Janssen Pharmaceuticals, Inc, Myriad Genetics, Inc., Schering, Elan, and Wyeth.

A.H. is a recipient of research grants from Pfizer Inc, Eisai Inc, and Forest Pharmaceuticals, Inc and is a consultant for Dainippon Sumitomo Pharma Co., Ortho-McNeill-Janssen Pharmaceuticals, Inc, Novartis Pharmaceuticals Corporation, and GlaxoSmithKline PLC. E.M.S., Y.X., and K.A. were employees of Pfizer Inc at the time of the analyses. M.M., C.A.P., and J.S. were employees of Eisai Inc at the time of the analyses.

Some peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he is the recipient of grants or research funding from Pfizer, Novartis and Sonexa Therapeutics; that he is a consultant or advisor to Pfizer, Novartis, Sonexa, AFFiRiS, Astellas, Servier, Schering- Plough, Wyeth, Lundbeck, Bristol Myers Squibb and UBC Peer Reviewer 2 has disclosed no relevant financial relationships.

Acknowledgments

The authors would like to acknowledge the invaluable contribution of the principal investigators in the original trials as listed previously10–12. In the development of this manuscript, editorial support was provided by Lisa Thomas, PhD, and Richard Daniel, PhD, of PAREXEL and was funded by Eisai Inc. and Pfizer Inc.