PRIZE ET Sub-Study

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

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.

Study Overview

• Status: Completed
• Conditions: Microvascular Angina
• Intervention / Treatment: Diagnostic test: Blood tests including genotyping; Diagnostic test: Exercise Tolerance Test

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: George Abraham; Phone Number: 01223638000; Email: george.abraham@nhs.net

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 0AY
    • Royal Papworth Hospital NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

1. Age >18 years.

2. 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)
3. Able to comply with study procedures.
4. Screen failure for the main PRIZE study
5. Written informed consent.

Exclusion criteria:

1. Lack of informed consent for the PRIZE ET Sub-study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with microvascular angina; Patients with clinical features of microvascular angina screened for the main PRIZE trial however not possessing the PHACTR1 GG minor allele single nucleotide polymorphism	Diagnostic test: Blood tests including genotyping; 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; Diagnostic test: Exercise Tolerance Test; Treadmill exercise test using the Bruce protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	correlation will be assessed at baseline at the start of the trial (time point 0)

Collaborators and Investigators

• Sponsor: Papworth Hospital NHS Foundation Trust
• Collaborators: NHS Greater Glasgow and Clyde
• Investigators: Principal Investigator: Stephen Hoole, Royal Papworth NHS Foundation Trust

Publications and helpful links

General Publications

• Abraham GR, Morrow AJ, Oliveira J, Weir-McCall JR, Davenport EE, Berry C, Davenport AP, Hoole SP. Mechanistic study of the effect of Endothelin SNPs in microvascular angina - Protocol of the PRIZE Endothelin Sub-Study. Int J Cardiol Heart Vasc. 2022 Feb 25;39:100980. doi: 10.1016/j.ijcha.2022.100980. eCollection 2022 Apr.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2021
• Primary Completion (Actual): August 13, 2022
• Study Completion (Actual): August 13, 2022

Study Registration Dates

• First Submitted: June 21, 2020
• First Submitted That Met QC Criteria: August 10, 2020
• First Posted (Actual): August 11, 2020

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: April 1, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: angina; endothelin receptor antagonist; zibotentan
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Angina Pectoris; Microvascular Angina
• Other Study ID Numbers: P02664

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be entered on electronic clinical record forms inputed on the Open Clinica eCRF platform with password protected access for researchers and for quality assurance personnel only.
• IPD Sharing Time Frame: A combined analysis with other leftover patient samples from other PRIZE trial participating sites is in progress. It is anticipated the clinical study report will be available in February 2024
• IPD Sharing Access Criteria: Individual participant data will not be shared routinely in this or any related research.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No