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

• Published in: The American heart journal Vol. 229; pp. 70 - 80
• Main Authors: Morrow, Andrew J, Ford, Thomas J, Mangion, Kenneth, Kotecha, Tushar, Rakhit, Roby, Galasko, Gavin, Hoole, Stephen, Davenport, Anthony, Kharbanda, Rajesh, Ferreira, Vanessa M, Shanmuganathan, Mayooran, Chiribiri, Amedeo, Perera, Divaka, Rahman, Haseeb, Arnold, Jayanth R., Greenwood, John P., Fisher, Michael, Husmeier, Dirk, Hill, Nicholas A, Luo, Xiaoyu, Williams, Nicola, Miller, Laura, Dempster, Jill, Macfarlane, Peter W, Welsh, Paul, Sattar, Naveed, Whittaker, Andrew, Connachie, Alex Mc, Padmanabhan, Sandosh, Berry, Colin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2020; Elsevier Limited; Mosby
• Subjects: Adult; Alleles; Angina; Angina pectoris; Biomarkers; Blood vessels; Cardiology; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - adverse effects; Cardiovascular disease; Cardiovascular diseases; Coronary artery disease; Coronary vessels; Double-Blind Method; Endothelin 1; Endothelin Receptor Antagonists - administration & dosage; Endothelin Receptor Antagonists - adverse effects; Endothelium; Female; Gene expression; Gene frequency; Gene polymorphism; Genetic Testing - methods; Health services; Heart diseases; Heart failure; Humans; Ischemia; Male; Medical imaging; Medical research; Medicine; Microvascular Angina - diagnosis; Microvascular Angina - drug therapy; Microvascular Angina - genetics; Microvasculature; Nucleotides; Patients; Polymorphism; Polymorphism, Single Nucleotide; Population; Population genetics; Population studies; Precision medicine; Precision Medicine - methods; Pyrrolidines - administration & dosage; Pyrrolidines - adverse effects; Randomized Controlled Trials as Topic; Receptor, Endothelin A - genetics; Single-nucleotide polymorphism; Teaching hospitals; Treadmills; Treatment Outcome; Trial Design
• ISSN: 0002-8703; 1097-6744; 1097-6744
• DOI: 10.1016/j.ahj.2020.07.007

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. 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 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. 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.