Clinical trial NCT04508998: PRIZE ET Sub-Study
Official title: Mechanistic Study of the Effect of ET-1 SNPs in Coronary Microvascular Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Microvascular Angina
Keywords: angina
endothelin receptor antagonist
zibotentan
Lead sponsor: Papworth Hospital NHS Foundation Trust
Sponsor class: OTHER_GOV
Collaborators: name: NHS Greater Glasgow and Clyde
First posted: 2020-08-11
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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:

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

Primary outcomes:
measure: 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)
timeFrame: correlation will be assessed at baseline at the start of the trial (time point 0)
Secondary outcomes:
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Royal Papworth Hospital NHS Foundation Trust
Study officials:
affiliation: Royal Papworth NHS Foundation Trust
name: Stephen Hoole
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.