Quantitative analysis of the placebo response in pharmacotherapy of insomnia and its application in clinical trials

Abstract Study Objectives This study aimed to develop a robust placebo response model for the pharmacotherapy for insomnia to guide drug development and clinical practice. Methods PubMed, EMBASE, and Cochrane Library databases were systematically searched for randomized placebo-controlled trials of medications for insomnia dating from the inception dates of the databases to April 18, 2018. Three placebo response models were established to describe the time–course of sleep parameters measured by objective (polysomnography or actigraphy) or subjective methods (sleep diary or questionnaires). The established models were applied to simulate placebo response distribution under different conditions using Monte Carlo simulations. Results Fifty-four studies involving 6,416 subjects were included. Placebo response increased over time and reached a plateau at approximately 8 weeks from start of therapy. Established models described the observed data reasonably well based on various diagnostic plots. Baseline sleep parameters affected the placebo response. There were significant positive correlations with placebo response and the severity of sleep latency, wake after sleep onset, and total sleep time at baseline. In addition, placebo response, assessed by subjective and objective methods, was consistent after correcting the baseline levels. Conclusions The established placebo response models can serve as a tool to predict placebo response at different baseline levels, which can provide valuable reference for clinical trial design, decision-making in drug development, and clinical practice.