Trial Refresh: A Case for an Adaptive Platform Trial for Pulmonary Exacerbations of Cystic Fibrosis

Abstract

Cystic fibrosis is a genetic disease typically characterized by progressive lung damage and premature mortality. Pulmonary exacerbations, or flare-ups of the lung disease, often require hospitalization for intensive treatment. Approximately 25% of patients with cystic fibrosis do not recover their baseline lung function after pulmonary exacerbations. There is a relative paucity of evidence to inform treatment strategies for exacerbations. Compounding this lack of evidence, there are a large number of treatment options already as well as becoming available. This results in significant variability between medication regimens prescribed by different physicians, treatment centers and regions with potentially adverse impact to patients. The conventional strategy is to undertake essential randomized clinical trials to inform treatment decisions and improve outcomes for patients with exacerbations. However, over the past several decades, clinical trials have generally failed to provide information critical to improved treatment and management of exacerbations. Bayesian adaptive platform trials hold the promise of addressing clinical uncertainties and informing treatment. Using modeling and response adaptive randomization, they allow for the evaluation of multiple treatments across different management domains, and progressive improvement in patient outcomes throughout the course of the trial. Bayesian adaptive platform trials require substantial amounts of preparation. Basic preparation includes extensive stakeholder involvement including elicitation of consumer preferences and clinician understanding of the research topic, defining the research questions, determining the best outcome measures, delineating study sub-groups, in depth statistical modeling, designing end-to-end digital solutions seamlessly supporting clinicians, researchers and patients, constructing randomisation algorithms and importantly, defining pre-determined intra-study end-points. This review will discuss the motivation and necessary steps required to embark on a Bayesian adaptive platform trial to optimize medication regimens for the treatment of pulmonary exacerbations of cystic fibrosis.