PRIZE ET Sub-Study
Study Details
Study Description
Brief Summary
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 |
|---|---|---|
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N/A |
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 Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- 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) [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.
Eligibility Criteria
Criteria
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:
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Age >18 years.
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Microvascular angina as defined by probable or definitive COVADIS criteria.
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Able to comply with study procedures.
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Written informed consent.
Exclusion Criteria:
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Non-cardiovascular exercise-limiting problem e.g. morbid (or severe) obesity (BMI ≥40.0 kg/m2)
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Genotype not available
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Women who are pregnant, breast-feeding or of child-bearing potential (WoCBP) without a negative pregnancy test and who are unwilling or unable to use highly effective contraception for the duration of the study treatment and 30 days after the last dose of study drug.
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Men who are sexually active with a WoCBP who are unwilling to use condoms or other highly effective methods of contraception for the duration of study treatment and for 14 weeks after last dose of study drug.
Where applicable, patients will be provided with advice on contraception and our definition of highly effective contraception is taken from previously published guidance from the MHRA and Faculty of Sexual and Reproductive Healthcare (FSRH): advised contraception methods include the copper intrauterine device, the levonorgestrel-releasing intrauterine system and the progestogen implant (as long as the woman is not taking a medication that may reduce the effectiveness of the implant). If a combined hormonal method, progestogen only pill or injection is chosen, then, due to the typical failure rates of these methods, the additional use of a barrier method such as the male condom will be advised.
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Heart failure (New York Heart Association Grade ≥II i.e. mild symptoms and slight limitation during ordinary activity)
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Recent (<3 months) myocardial infarction
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A history of epilepsy, other CNS adverse events, neurological symptoms or signs consistent with spinal cord compression or CNS metastases.
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Moderate or more severe renal impairment (GFR < 45 mL/min)
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Liver disease with a Child-Pugh score of A (5-6 points) or higher
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Participation in another intervention study involving a drug within the past 90 days or 5 half-lives whichever is longer (co-enrolment in observational studies is permitted).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Royal Papworth Hospital NHS Foundation Trust | Cambridge | United Kingdom | CB2 0AY |
Sponsors and Collaborators
- Papworth Hospital NHS Foundation Trust
- NHS Greater Glasgow and Clyde
Investigators
- Principal Investigator: Stephen Hoole, Royal Papworth NHS Foundation Trust
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- P02664