Personalized Prediction of Alzheimer’s Disease and Its Treatment Effects by Donepezil: An Individual Participant Data Meta-Analysis of Eight Randomized Controlled Trials

Article type: Research Article

Authors: Yoshida, Kazufumi^{a; *} | Seo, Michael^{b; c} | Luo, Yan^a | Sahker, Ethan^{a; d} | Cipriani, Andrea^{e; f} | Leucht, Stefan^g | Iwatsubo, Takeshi^h | Efthimiou, Orestis^{c; e; i} | Furukawa, Toshiaki A.^a

Affiliations: [a] Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine / School of Public Health, Kyoto, Japan | [b] Graduate School for Health Sciences, University of Bern, Bern, Switzerland | [c] Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland | [d] Population Health and Policy Research Unit, Medical Education Center, Kyoto University Graduate School of Medicine, Kyoto, Japan | [e] Department of Psychiatry, University of Oxford, Oxford, United Kingdom | [f] Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, United Kingdom | [g] Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich, Germany | [h] Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan | [i] Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland

Correspondence: [*] Correspondence to: Kazufumi Yoshida, MD, MSc, Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine / School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: +81 75 753 9491; Fax: +81 75 753 4641; E-mail: [email protected].

Abstract: Background:Patient characteristics may predict the progression of Alzheimer’s disease (AD) and may moderate the effects of donepezil. Objective:To build a personalized prediction model for patients with AD and to estimate patient-specific treatment effects of donepezil, using individual patient characteristics. Methods:We systematically searched for all double-masked randomized controlled trials comparing oral donepezil and pill placebo in the treatment of AD and requested individual participant data through its developer, Eisai. The primary outcome was cognitive function at 24 weeks, measured with the Alzheimer’s Disease Assessment Scale-cognitive component (ADAS-cog). We built a Bayesian meta-analytical prediction model for patients receiving placebo and we performed an individual patient data meta-analysis to estimate patient-level treatment effects. Results:Eight studies with 3,156 participants were included. The Bayesian prediction model suggested that more severe cognitive and global function at baseline and younger age were associated with worse cognitive function at 24 weeks. The individual participant data meta-analysis showed that, on average, donepezil was superior to placebo in cognitive function (ADAS-cog scores, –3.2; 95% Credible Interval (CrI) –4.2 to –2.1). In addition, our results suggested that antipsychotic drug use at baseline might be associated with a lower effect of donepezil in ADAS-cog (2.0; 95% CrI, –0.02 to 4.3). Conclusion:Although our results suggested that donepezil is somewhat efficacious for cognitive function for most patients with AD, use of antipsychotic drugs may be associated with lower efficacy of the drug. Future research with larger sample sizes, more patient covariates, and longer treatment duration is needed.

Keywords: Alzheimer’s disease, cognition, donepezil, effect modifier, meta-analysis, prognosis

DOI: 10.3233/JAD-220263

Journal: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1143-1157, 2022