Quantifying placebo responses in clinical evaluation of neuropsychiatric symptoms in Alzheimer’s disease
This study aimed to establish a non-linear mixed effects model to quantitatively analyze the placebo responses of neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD).
A comprehensive literature search was conducted in public databases. Placebo-controlled randomized AD clinical trials using the neuropsychiatric inventory (NPI) score as the primary or secondary outcome were included. Non-linear mixed effects model was used to describe the time course of the placebo responses of NPS in AD clinical trials. Potential affecting factors were tested as covariates.
A total of 32 clinical studies (involving 3942 subjects) were included in model-based analysis. We found that the maximal placebo responses of NPS were reached at week 4 approximately, after which rebound effects appeared. The baseline NPI score had a significant impact on the placebo responses. Higher baseline NPI score tended to cause greater reductions in NPI score at week 8 and a smaller degree of rebound. For AD patients whose normalized baseline NPI score was 10 points and 30 points, the reduction in normalized NPI score at week 8 was estimated to be 0.83 and 7.43 points, respectively; and the rebound rate after week 8 was estimated to be 0.1 points/week and 0.08 points/week, respectively.
The duration of 4 weeks is sufficient to determine the drug efficacy for assessing NPS in AD clinical trials. The baseline NPI score was a key factor associated with placebo responses of NPS, which should be considered when designing future clinical trials and conducting comparisons across trials.
KeywordsAlzheimer’s disease Neuropsychiatric symptoms Placebo responses Model-based meta-analysis Clinical trial design
The authors wish to acknowledge the participants and their study partners who volunteered their time to complete this study.
This study was supported by the Science and Technology Innovation Action Plan of Shanghai (17401970900), National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Thirteenth Five-year Plan Period (2018ZX09734-005, 2018ZX09711001-009-011, 2018ZX09731016-001, 2017ZX09304003), and Research Program of Shanghai University of traditional Chinese Medicine (2016YSN15).
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
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