Model-informed Approach to Estimate Treatment Effect in Placebo-controlled Clinical Trials Using an Artificial Intelligence-based Propensity Weighting Methodology to Account for Non-specific Responses to Treatment

In randomized, placebo controlled clinical trials (RCT) in major depressive disorders (MDD), treatment response (TR) is estimated by the change from baseline at study-end (EOS) of the scores of clinical scales used for assessing disease severity. Treatment effect (TE) is estimated by the baseline-adjusted difference at EOS of TR between active treatments and placebo.The TE is function of treatment-specific and, non-specific (NSRT) effect (referred as placebo effect), and placebo response. The conventional statistical approaches used to estimate TE does not account for the potentially confounding effect of NSRT. This pragmatic approach is equivalent to assume that TE is independent of NSRT even if this assumption is not true, leading to potential risks of inflating false negative/positive results in presence of high proportion of subjects with high/low NSRT.The objective of this study was to develop a model informed framework to analyze the outcomes of RCTs using data driven models, non-linear-mixed effect approach, artificial intelligence, and propensity score weighted methodology (PSW) to control the confounding effect of treatment non-specific response on the estimated TE. The secondary objective was to explore the impact of relevant covariates (including the assessment of a dose-response relationship) on the outcomes of pooled data from two RCTs.The proposed PSW approach provides a critical tool for controlling the confounding effect of treatment non-specific response, to increase signal detection and to provide a reliable estimate of the 'true' treatment effect by controlling false negative results associated with excessively high treatment non-specific response.