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NCT Number: NCT04508998

PRIZE ET Sub-Study

Microvascular angina (MVA) is caused by abnormalities of the small blood vessels in the heart. Endothelin-1 (ET-1) is a chemical messenger that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken over a long period, especially as levels of ET-1 increase. As a result, patients experience pain, psychological distress and limitation of their daily activities.

Cambridge is a participating recruitment site for a large randomised, double blinded, placebo controlled crossover trial (the PRIZE study: NCT04097314) investigating Zibotentan as a new drug treatment for patients with MVA using a 'precision medicine' approach. Zibotentan is a drug originally developed by Astra Zeneca for prostate cancer but prior research has shown that it acts to relax the small blood vessels of patients with MVA, highlighting its potential as a novel therapy for this patient group. The PRIZE study population will be enriched for 'responders' to the drug by screening patients with MVA for a gene mutation known to increase levels of circulating endothelin. The trial aims to initially invite approximately 356 participants for genetic testing but only 100 participants will go forward into the main study, with approximately 2/3rd being screen failures.

In our sub-study, we will invite patients with MVA who are screen failures at our site for further blood tests looking for other genetic variants in the ET-1 signalling pathway and examine how this correlates with the severity of microvascular angina quantified by cardiac MRI and clinical assessments. Data from this sub-study would provide a bio-resource for further analysis of the main PRIZE trial to identify other patients that would benefit from Zibotentan.

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Key information

Conditions

Microvascular Angina Angina Pectoris Cardiovascular Diseases Chest Pain Heart Diseases Myocardial Ischemia Neurologic Manifestations Pain Pathological Conditions, Signs and Symptoms Signs and Symptoms Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Royal Papworth Hospital NHS Foundation Trust

Cambridge, CB2 0AY, United Kingdom

About this study

Patients with microvascular angina (MVA) are under-diagnosed and have limited therapeutic options available to them. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the small vessel obstruction that causes MVA. The PRIZE trial will apply a precision medicine approach to assess the therapeutic effect of Zibotentan, an ET-1 antagonist (ETA) selective for the ETA receptor in patients who are high ET-1 expressors (possessing the PHACTR1 minor GG allele single nucleotide polymorphism - SNP). Unfortunately, the incidence of this SNP occurs in only a third of the population, resulting in a high screen-failure rate.

In the proposed sub-study, we aim to recruit patients with MVA but without the minor GG allele SNP to potentially identify other potential 'responders' to Zibotentan. In an observational mechanistic study, we will perform baseline genotyping for other genetic variants in the ET-1 pathway as well as phenotyping patients by quantification of microvascular disease from retrospective analysis of cardiac MRI data. Patients will also complete angina and quality of life questionnaires and perform an exercise stress test to determine maximal exercise distance. Information from this sub-study will provide a genotype bio-resource that could identify novel SNPs for the pathogenesis of MVA that could be validated in the UK biobank. This may indicate other ETA receptor antagonist super-responders, justifying treatment with Zibotentan and enabling more patients with MVA to potentially benefit from this promising drug.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Patients who after screening blood tests and clinical assessment are ineligible for the main PRIZE trial will qualify for this study. Patients will be screened for the PRIZE trial according to the following:

Inclusion criteria

  • Age >18 years.
  • Probable or definite Microvascular Angina as defined in COVADIS criteria:
  • Clinical symptoms of angina
  • No obstructive coronary artery disease
  • Objective evidence of myocardial ischemia
  • Evidence of impaired coronary microvascular function (Optional)
  • Able to comply with study procedures.
  • Screen failure for the main PRIZE study
  • Written informed consent.

Exclusion criteria

  • Lack of informed consent for the PRIZE ET Sub-study

Treatment and study plan

Blood tests including genotyping

Diagnostic Test

Blood tests for alternative SNPs altering levels of ET-A receptor expression; blood will be further analysed for endothelin receptor mRNA and other plasma peptides important in the endothelin signalling pathway

Exercise Tolerance Test

Diagnostic Test

Treadmill exercise test using the Bruce protocol

Primary outcomes

  1. Correlation of ET-A SNPs with ET-A expression in blood by qPCR, levels of endothelin related plasma peptides and clinical data (exercise duration and microvascular disease measured by quantitative perfusion on Cardiac MRI)

    Time frame: correlation will be assessed at baseline at the start of the trial (time point 0)

    Measurement of molecules associated with the endothelin signalling pathway in patients with different SNPs for the ET-A receptor will be compared with phenotypic characteristics of the patients, specifically exercise tolerance and by retrospective analysis of the patient's cardiac MRI using quantitative measures of myocardial blood flow.

Sponsors and collaborators

Lead sponsor

Papworth Hospital NHS Foundation Trust

Other Gov

Collaborators

  • NHS Greater Glasgow and Clyde

Registry information

Official study title

Mechanistic Study of the Effect of ET-1 SNPs in Coronary Microvascular Disease

Important dates

Study start
2021
Primary completion
2022
Study completion
2022
First posted
Aug 11, 2020
Registry last updated
Apr 4, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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