The StratosPHere 2 trial is underway to evaluate the efficacy of hydroxychloroquine and glycerol phenylbutyrate in treating pulmonary hypertension associated with mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene. This study is a response-adaptive, randomized, placebo-controlled trial designed to assess the impact of these repurposed drugs on BMPR2 target engagement in patients with specific BMPR2 mutations.
Trial Design and Objectives
The trial will enroll approximately 40 participants, with 20 patients in each of two mutation strata: missense and haploinsufficiency. Participants will be recruited from nationally designated specialist respiratory centers in the UK. The primary objective is to determine whether hydroxychloroquine and phenylbutyrate can modulate BMPR2 function in vivo, as measured by a change in a novel composite panel of BMPR2 target genes in peripheral blood.
Interventions
Participants will be randomized to one of three arms:
- T1: Hydroxychloroquine + Standard of Care
- T2: Glycerol Phenylbutyrate + Standard of Care
- C: Placebo + Standard of Care
Hydroxychloroquine sulphate will be administered as film-coated tablets, while glycerol phenylbutyrate will be given as a liquid. The control arm will consist of matching placebos to maintain blinding. Treatments will be administered daily in addition to standard of care.
Outcomes
The primary outcome is the change in peripheral blood-based BMPR2 function (ΔBMPR2) from baseline to 8-week follow-up. This will be assessed using a novel composite panel defined by the change in gene expression of eight biomarkers: ID3, SMAD1, SMAD5, NOTCH1, NOTCH2, ID2, ARL4C, and PTGS2, measured via quantitative PCR (qPCR).
Secondary outcomes include:
- Safety, as defined by the incidence and severity of adverse events.
- Efficacy, as defined by changes in functional measures such as the 6-minute walk test, NT-proBNP levels, and health-related quality of life (EMPHASIS-10).
- BMPR2 cell surface protein expression on peripheral blood white cells.
- Changes in individual qPCR biomarker expression and RNAseq peripheral blood expression.
Statistical Analysis and Sample Size
The trial employs a Bayesian response-adaptive design, allowing for the dynamic allocation of patients to treatment arms based on emerging data. Sample size evaluation was conducted using simulations based on data from the StratosPHere 1 study. The study is designed to detect a 30% change in the primary endpoint, with a type-I error control at 10% and 80% power, assuming one superior treatment arm per stratum. A one-sided non-parametric Wilcoxon test will be used for the final analysis.
Safety Considerations
Safety is a paramount concern, with predefined criteria for discontinuing or modifying allocated interventions. These include the development of adverse events, meeting specific blood parameter safety criteria, and the use of prohibited concomitant therapies. Subjects will be closely monitored for potential visual disturbances related to hydroxychloroquine, and serum digoxin levels will be monitored in patients receiving combined therapy.
Significance
The StratosPHere 2 trial represents a significant effort to identify effective treatments for pulmonary hypertension associated with BMPR2 mutations. By employing a response-adaptive design and focusing on target engagement biomarkers, the trial aims to provide valuable insights into the potential of hydroxychloroquine and phenylbutyrate to improve outcomes for this patient population.
