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

ABSTRACT: 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 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.

SUBMITTER: Morrow AJ

PROVIDER: S-EPMC7674581 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Morrow Andrew J AJ Ford Thomas J TJ Mangion Kenneth K Kotecha Tushar T Rakhit Roby R Galasko Gavin G Hoole Stephen S Davenport Anthony A Kharbanda Rajesh R Ferreira Vanessa M VM Shanmuganathan Mayooran M Chiribiri Amedeo A Perera Divaka D Rahman Haseeb H Arnold Jayanth R JR Greenwood John P JP Fisher Michael M Husmeier Dirk D Hill Nicholas A NA Luo Xiaoyu X Williams Nicola N Miller Laura L Dempster Jill J Macfarlane Peter W PW Welsh Paul P Sattar Naveed N Whittaker Andrew A Connachie Alex Mc AM Padmanabhan Sandosh S Berry Colin C

American heart journal 20200717

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 ET<sub>A</sub> receptor. We have identified z ...[more]

PMID: 32942043

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Project description:The Medical Research Councils' framework for complex interventions has been criticized for not including theory-driven approaches to evaluation. Although the framework does include broad guidance on the use of theory, it contains little practical guidance for implementers and there have been calls to develop a more comprehensive approach. A prospective, theory-driven process of intervention design and evaluation is required to develop complex healthcare interventions which are more likely to be effective, sustainable and scalable.We propose a theory-driven approach to the design and evaluation of complex interventions by adapting and integrating a programmatic design and evaluation tool, Theory of Change (ToC), into the MRC framework for complex interventions. We provide a guide to what ToC is, how to construct one, and how to integrate its use into research projects seeking to design, implement and evaluate complex interventions using the MRC framework. We test this approach by using ToC within two randomized controlled trials and one non-randomized evaluation of complex interventions.Our application of ToC in three research projects has shown that ToC can strengthen key stages of the MRC framework. It can aid the development of interventions by providing a framework for enhanced stakeholder engagement and by explicitly designing an intervention that is embedded in the local context. For the feasibility and piloting stage, ToC enables the systematic identification of knowledge gaps to generate research questions that strengthen intervention design. ToC may improve the evaluation of interventions by providing a comprehensive set of indicators to evaluate all stages of the causal pathway through which an intervention achieves impact, combining evaluations of intervention effectiveness with detailed process evaluations into one theoretical framework.Incorporating a ToC approach into the MRC framework holds promise for improving the design and evaluation of complex interventions, thereby increasing the likelihood that the intervention will be ultimately effective, sustainable and scalable. We urge researchers developing and evaluating complex interventions to consider using this approach, to evaluate its usefulness and to build an evidence base to further refine the methodology.Clinical trials.gov: NCT02160249.

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Dataset Information

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

Publications

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

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