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Defining Treatment Response to Donepezil in Alzheimer’s Disease

Responder Analysis of Patient-Level Data from Randomized, Placebo-Controlled Studies

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Abstract

Background: Defining treatment success in progressive diseases, such as Alzheimer’s disease (AD), can be challenging.

Objective: To explore the impact of employing different criteria to define a treatment ‘responder’ using analyses of patient-level data from randomized, placebo-controlled studies of donepezil in AD.

Methods: Trials were included in the analysis if they met several criteria, including the following: randomized, placebo-controlled trial of donepezil 10 mg/day in mild-to-moderate AD; cognition measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) or Mini-Mental State Examination (MMSE); and a 24-week endpoint and outcomes that included global assessments. Definitions of response were: improvements in cognition plus one other domain; improvement in cognition only; improvement or improvement/no change in global response; and improvement/stabilization/less than expected decline by ≤2 or ≤4 or ≤6 points on the ADAS-cog.

Results: Five studies identified from the literature search met the specified criteria for inclusion. The response to donepezil measured by ADAS-cog varied from 26% to 63% and that of placebo from 14% to 47%, depending on the definition of improvement used. For definitions that included a less than expected decline on ADAS-cog, the more modest the effect defined, the less the drug versus placebo difference and the higher the percentage of patients meeting this definition.

Conclusions: The definition of treatment ‘response’ in a progressive neurodegenerative disease can encompass a variety of outcomes, including short-term improvement, longer-term stabilization and a slowed decline in one or more clinically relevant symptoms or symptom domains. The ability to identify groups of people who respond to donepezil underscores the clinical utility of the medication and may contribute to more focused assessments of the cost effectiveness of cholinesterase inhibitors.

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Acknowledgements

All of the authors are employees of Eisai or Pfizer except Alistair Burns, who acted as a paid consultant in connection with the development of this manuscript and who carries out consultancy work for pharmaceutical companies, including Eisai and Pfizer, involved in the manufacture and distribution of drugs for Alzheimer’s disease. Co-authors from Eisai Europe Ltd and Pfizer Inc. funded and designed these analyses in response to specific requests from the UK National Institute for Health and Clinical Excellence and other reimbursement authorities. The statistical analysis was carried out by Symbiance, and was funded by Eisai and Pfizer. These analyses were provided to the primary author for review, interpretation and development of this manuscript.

As the primary author, Alistair Burns would like to thank Eisai/Pfizer for providing the data enabling him to write this paper. The authors would also like to acknowledge the editorial administration support provided by L. Thomas, PhD, of PAREXEL, which was funded by Eisai Europe Ltd and Pfizer Inc.

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Authors and Affiliations

  1. 2nd Floor, Education and Research Centre, Wythenshawe Hospital, University of Manchester, Manchester, M23 9PL, UK

    Alistair Burns (Professor of Old Age Psychiatry)

  2. Eisai Europe Ltd, London, UK

    Andrew Yeates

  3. Eisai Corporation of North America, Woodcliff Lake, New Jersey, USA

    Latif Akintade

  4. Pfizer Inc, New York, New York, USA

    Megan del Valle, Richard Y. Zhang & Elias M. Schwam

  5. Eisai Medical Research, Ridgefield Park, New Jersey, USA

    Carlos A. Perdomo

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  1. Alistair Burns
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  2. Andrew Yeates
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  3. Latif Akintade
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  4. Megan del Valle
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  7. Carlos A. Perdomo
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Correspondence to Alistair Burns.

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Burns, A., Yeates, A., Akintade, L. et al. Defining Treatment Response to Donepezil in Alzheimer’s Disease. Drugs Aging 25, 707–714 (2008). https://doi.org/10.2165/00002512-200825080-00007

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