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. 2024 Oct 15;25(1):680.
doi: 10.1186/s13063-024-08485-z.

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

Nina Deliu  1   2 , Rajenki Das  3 , Angelique May  4 , Joseph Newman  4   5 , Jo Steele  6 , Melissa Duckworth  6 , Rowena J Jones  4 , Martin R Wilkins  7 , Mark R Toshner  4   5 , Sofia S Villar  3
Affiliations

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

Nina Deliu et al. Trials. .

Abstract

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).

Keywords: Adaptive design; BMPR2 mutations; Bayesian response-adaptive randomisation; Phase II trial; Precision medicine; Pulmonary arterial hypertension.

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Conflict of interest statement

Authors of this paper have been part of advisory boards and safety committees for PhaseV, MorphogenIX, VIVUS, Janssen, Acceleron, GSK, Novartis, ComCov and, FluCov. Are disclosed consultancies to Cheisi, Aerami, Benevolent AI, Jansen, Apollo Therapeutics and, Merck. Travel support has been received from Aparito Ltd, United Therapeutics, Apollo Therapeutics, GSK, Jansen and, Pulmonary Vascular Research Institute.

Figures

Fig. 1
Fig. 1
Schematic of the StratosPHere 2 trial design. A = “missense” and B = “haploinsufficiency” denote the two mutation strata; n denotes the sample size, with nA,1 being the sample size of the mutation stratum A at stage 1. T1, T2 and C denote the two active arms and the control arm, respectively. *The probability threshold for dropping an active arm (either T1 or T2, but not C) will be detailed internally and disclosed at the end of the study to ensure PIs do not predict the algorithm’s allocations
See this image and copyright information in PMC

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