Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial

Andrew Morrow ,Dirk Husmeier,Alex Mc Connachie,Amedeo Chiribiri,Paul Welsh,Rajesh Kharbanda,Divaka Perera,Jayanth R Arnold,Jill Dempster,Gavin Galasko,Mayooran Shanmuganathan,Xiaoyu Luo,Haseeb Rahman,Michael Fisher,Kenneth Mangion,Roby Rakhit,Nicola Williams,Tushar Kotecha,Sandosh Padmanabhan,Naveed Sattar,Nicholas A Hill ,Peter W Macfarlane ,Andrew K Whittaker ,Tom Ford ,Anthony P Davenport ,Vanessa M Ferreira ,Stephen P Hoole ,John P Greenwood ,Lee A Miller

doi:10.1016/j.ahj.2020.07.007

Abstract

BackgroundMicrovascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina.MethodsWe will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan.The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo.ConclusionPRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Highlights

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated
The study population will be enriched to ensure the G-allele frequency of the rs9349379 single nucleotide polymorphism (SNP) is at least 50%
The trial is designed to assess the superiority of the addition of oral zibotentan to guideline-indicated therapy as compared with placebo and guidelineindicated treatment for patients with microvascular angina. (Figure 2)

Summary

Introduction

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. The management of patients with angina pectoris focuses on detection and treatment of flowlimiting epicardial coronary artery disease (CAD).[3]. Fewer than half of patients with suspected angina have evidence of obstructive CAD on coronary angiography.[4,5] Many patients with “normal” coronary angiography have signs, symptoms and investigations inkeeping with myocardial ischemia –this is termed ischemia with non-obstructive coronary artery disease (INOCA).[6]. A growing body of evidence supports the differentiation of this group into distinct disease endotypes—the most common being microvascular angina and epicardial coronary vasospasm—that are amenable to stratified medicine.[3,8]

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