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3 Rationale and design of the Medical Research Council Precision medicine with Zibotentan in microvascular angina (PRIZE) trial MRI sub-study
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  1. Andrew Morrow,
  2. Thomas J Ford1,2,
  3. Robert Sykes1,
  4. Kenneth Mangion1,
  5. Tushar Kotecha4,
  6. Roby Rakhit4,
  7. Gavin Galasko5,
  8. Stephen Hoole6,
  9. Anthony Davenport7,
  10. George Abraham7,
  11. Rajesh Kharbanda8,
  12. Vanessa Ferreira8,
  13. Amedeo Chiribiri9,
  14. Divaka Perera10,
  15. Haseeb Raman10,
  16. Jayanth R Arnold11,
  17. John P Greenwood12,
  18. Michael Fisher13,
  19. Dirk Husmeier3,
  20. Nicholas A Hill3,
  21. Xiaoyu Luo3,
  22. Nicola Williams14,
  23. Laura Miller14,
  24. Jill Dempster1,
  25. Peter W Macfarlane1,
  26. Paul Welsh1,
  27. Naveed Sattar1,
  28. Andrew Whittaker15,
  29. Alex McConnachie16,
  30. Sandosh Padmanabhan1,
  31. Colin Berry1
  1. 1British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
  2. 2University of New South Wales, Sydney, Australia
  3. 3School of Mathematics and Statistics, University of Glasgow, Glasgow, UK
  4. 4Royal Free Hospital, Royal Free London NHS Foundation Trust London, UK
  5. 5Lancashire Cardiac Centre, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK
  6. 6Department of Interventional Cardiology, Royal Papworth Hospital, Cambridge, UK
  7. 7Clinical Pharmacology, University of Cambridge, Cambridge, UK
  8. 8Radcliffe Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
  9. 9Division of Imaging Sciences, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK
  10. 10School of Cardiovascular Medicine and Sciences, King’s College London, London, UK
  11. 11Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
  12. 12Leeds University and Leeds Teaching Hospitals NHS Trust, Leeds, UK
  13. 13Liverpool University and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
  14. 14Department of Clinical Genetics, Queen Elizabeth University Hospital, Glasgow, UK
  15. 15Emerging Innovations Unit, Discovery Sciences, RandD, AstraZeneca, Cambridge, UK
  16. 16Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK

Abstract

Introduction Microvascular angina is caused by cardiac small vessel disease and dysregulation of the endothelin system is implicated. The chronic elevation of circulating ET-1 in microvascular angina may be influenced by genetic factors. 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 microvascular angina. 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.

The Precision medicine with Zibotentan in microvascular angina (PRIZE) trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. 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 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.

After randomisation in PRIZE, subjects will be invited to participate in the cardiac MRI sub-study. Myocardial perfusion is generally impaired in patients with microvascular angina. The rationale for undertaking this MRI sub-study is to determine whether, compared with placebo, treatment with zibotentan improves myocardial blood flow.

Methods Patients will undergo multiparametric CMR at three points (baseline prior to therapy and after each 12 week treatment phase). At each scan they will have assessments of myocardial blood flow (both rest and stress using the Kellman quantitative perfusion method), left ventricular function and mass, aortic stiffness assessment and tissue characterisation (T1 mapping (MOLLI and ShMOLLI), T2 mapping and late gadolinium enhancement imaging).

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 multicentre trial. The MRI sub-study contributes to this study by providing vital mechanistic and safety information.

https://doi.org/10.1136/heartjnl-2021-BSCMR.3

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