PRIZE ET Sub-Study
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| ClinicalTrials.gov Identifier: NCT04508998 |
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Recruitment Status :
Recruiting
First Posted : August 11, 2020
Last Update Posted : October 4, 2022
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Microvascular Angina | Diagnostic Test: Blood tests including genotyping Diagnostic Test: Exercise Tolerance Test | Not Applicable |
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 (Clinical Trial) |
| Estimated Enrollment : | 60 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Basic Science |
| Official Title: | Mechanistic Study of the Effect of ET-1 SNPs in Coronary Microvascular Disease |
| Actual Study Start Date : | May 14, 2021 |
| Estimated Primary Completion Date : | March 5, 2023 |
| Estimated Study Completion Date : | August 5, 2023 |
| Arm | Intervention/treatment |
|---|---|
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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
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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 |
- 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
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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:
1. Lack of informed consent for the PRIZE ET Sub-study
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04508998
| Contact: George Abraham | 01223638000 | george.abraham@nhs.net |
| United Kingdom | |
| Royal Papworth Hospital NHS Foundation Trust | Recruiting |
| Cambridge, United Kingdom, CB2 0AY | |
| Contact: George Abraham george.abraham@nhs.net | |
| Principal Investigator: | Stephen Hoole | Royal Papworth NHS Foundation Trust |
Publications:
| Responsible Party: | Papworth Hospital NHS Foundation Trust |
| ClinicalTrials.gov Identifier: | NCT04508998 |
| Other Study ID Numbers: |
P02664 |
| First Posted: | August 11, 2020 Key Record Dates |
| Last Update Posted: | October 4, 2022 |
| Last Verified: | October 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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. |
| Supporting Materials: |
Study Protocol Informed Consent Form (ICF) Clinical Study Report (CSR) |
| Time Frame: | Draft versions of study protocol and informed consent form have been shared since September 2020. It is anticipated the clinical study report will be available in February 2023 |
| Access Criteria: | Individual participant data will not be shared routinely in this or any related research. |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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angina endothelin receptor antagonist zibotentan |
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Microvascular Angina Angina Pectoris Myocardial Ischemia |
Heart Diseases Cardiovascular Diseases Vascular Diseases |