Application of Bayesian analyses to doubly randomized delayed start, matched control designs to demonstrate disease modification

Abstract

Disease modification is a primary therapeutic aim when developing treatments for most chronic progressive diseases. The best treatments do not simply affect disease symptoms but fundamentally improve disease course by slowing, halting, or reversing disease progression. One of many challenges for establishing disease modification relates to the identification of adequate analytic tools to show differences in a disease course following intervention. Traditional approaches rely on the comparisons of slopes or noninferiority margins. However, it has proven difficult to conclusively demonstrate disease modification using such approaches. To address these challenges, we propose a novel adaptation of the delayed start study design that incorporates posterior probabilities identified by hierarchical Bayesian inference approaches to establish evidence for disease modification. Our models compare the size of treatment differences at the end of the delayed start period with those at the end of the early start period. Simulations that compare several models are provided. These include general linear models, repeated measures models, spline models, and model averaging. Our work supports the superiority of model averaging for accurately characterizing complex data that arise in real world applications. This novel approach has been applied to the design of an ongoing, doubly randomized, matched control study that aims to show disease modification in young persons with schizophrenia (the Disease Recovery Evaluation and Modification (DREaM) study). The application of this Bayesian methodology to the DREaM study highlights the value of this approach and demonstrates many practical challenges that must be addressed when implementing this methodology in a real world trial.

Keywords: Bayesian; disease modification; doubly randomized delayed start; matched control designs.