Journal Article

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

Deliu, Nina, Das, Rajenki, Duckworth, Melissa, Villar, Sofia S., Newman, Joseph, Jones, Rowena J., Toshner, Mark R., Wilkins, Martin R., Steele, Jo, May, Angelique

2024

Overview

Background Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate. Methods This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease. Discussion The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease. Trial registration The study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adaptive design / Bayesian response-adaptive randomisation / Biomarkers / Biomedicine / Biostatistics / BMPR2 mutations / Bone Morphogenetic Protein Receptors, Type II - genetics / Bone morphogenetic proteins / Care and treatment / Clinical trials / Clinical Trials, Phase II as Topic / Collaboration / Complications and side effects / Costs / Drug dosages / Drug Repositioning / Familial Primary Pulmonary Hypertension - drug therapy / Familial Primary Pulmonary Hypertension - genetics / Familial Primary Pulmonary Hypertension - physiopathology / Female / Health aspects / Health Sciences / Hospitals / Humans / Hydroxychloroquine / Hydroxychloroquine - therapeutic use / Immunomodulators / Male / Medicine / Medicine & Public Health / Multicenter Studies as Topic / Mutation / Patient outcomes / Patients / Phase II trial / Phenylbutyrates - therapeutic use / Precision Medicine / Pulmonary arterial hypertension / Pulmonary Arterial Hypertension - drug therapy / Pulmonary Arterial Hypertension - genetics / Pulmonary Arterial Hypertension - physiopathology / Pulmonary arteries / Pulmonary hypertension / Randomized Controlled Trials as Topic / Statistics for Life Sciences / Study Protocol / Treatment Outcome