StratosPHere 2: statistical analysis plan for a response-adaptive randomised placebo-controlled phase II trial to evaluate hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2

Background: The StratosPHere 2 trial will evaluate the efficacy of hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2 by focussing on the novel biomarker and other endpoints including safety. Study design: StratosPHere 2 is a three armed, placebo-controlled, phase 2 trial with two strata based on the mutation groups. It is response adaptive where the allocation of treatments follows a Bayesian response-adaptive randomisation algorithm. An expected number of 20 patients will be randomised in each stratum to one of the three arms containing hydroxychloroquine, phenylbutyrate and placebo. The primary outcome is a novel endpoint considering the change in the bone morphogenetic receptor type 2 (BMPR2). Method: The final primary analysis on the efficacy of each active treatment against control is assessed using a one-sided nonparametric Wilcoxon test computed on the continuous biomarker data collected up to 8 weeks from the start of treatment. Discussion: This manuscript presents the key elements of the StratosPHere 2 implementation and statistical analysis plan. This is submitted to the journal before the first interim analysis to preserve the scientific integrity under a response-adaptive design framework. The StratosPHere 2 trial closely follows published guidelines for the content of Statistical Analysis Plans in clinical trials. Trial registration: The ISRCTN Registry ISRCTN10304915 (22/09/2023)