Rationale and design of the Medical Research Council precision medicine with Zibotentan in microvascular angina (PRIZE) trial

Morrow, A. J. et al. (2020) Rationale and design of the Medical Research Council precision medicine with Zibotentan in microvascular angina (PRIZE) trial. American Heart Journal, 229, pp. 70-80. (doi: 10.1016/j.ahj.2020.07.007) (PMID:32942043)

Abstract

Background: 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. 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. Methods: We 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 Precision medicine with Zibotentan in microvascular angina (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. Conclusion: PRIZE 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Berry, Professor Colin and Macfarlane, Professor Peter and McConnachie, Professor Alex and Davenport, Dr Anthony and Padmanabhan, Professor Sandosh and Ford, Thomas and Welsh, Professor Paul and Luo, Professor Xiaoyu and Dempster, Miss Jill and Hill, Professor Nicholas and Mangion, Dr Kenneth and Sattar, Professor Naveed and Husmeier, Professor Dirk and Morrow, Dr Andrew and Miller, Ms Laura
• Authors: Morrow, A. J., Ford, T. J., Mangion, K., Kotecha, T., Rakhit, R., Galasko, G., Hoole, S., Davenport, A., Kharbanda, R., Ferreira, V. M., Shanmuganathan, M., Chiribiri, A., Perera, D., Rahman, H., Arnold, J. R., Greenwood, J. P., Fisher, M., Husmeier, D., Hill, N. A., Luo, X., Williams, N., Miller, L., Dempster, J., Macfarlane, P. W., Welsh, P., Sattar, N., Whittaker, A., McConnachie, A., Padmanabhan, S., and Berry, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre; College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing; College of Science and Engineering > School of Mathematics and Statistics > Mathematics; College of Science and Engineering > School of Mathematics and Statistics > Statistics
• Journal Name: American Heart Journal
• Publisher: Elsevier
• ISSN: 0002-8703
• ISSN (Online): 1097-6744
• Published Online: 17 July 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in American Heart Journal 229: 70-80
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
303944		BHF Centre of Excellence	Rhian Touyz	British Heart Foundation (BHF)	RE/18/6/34217	CAMS - Cardiovascular Science
303684		A randomized, double-blind, placebo-controlled Phase 2A cross-over trial of oral zibotentan in patients with angina due to small vessel disease: a proof-of-concept, developmental trial for safety, efficacy and biomarkers development	Colin Berry	Medical Research Council (MRC)	MR/S018905/1	CAMS - Cardiovascular Science