Study of ET-1 SNP Effects on ET-1 Antagonism in Coronary Microvascular Disease

• Status: Not yet recruiting
• Trial end date: 2023-02-01
• Target enrollment: 60
• Participant gender: All

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 in the longer term, especially as levels of ET-1 increase. As a result, patients experience pain, psychological distress and limitation of their daily activities.

Originally developed by AstraZeneca for cancer treatment, prior research has confirmed that Zibotentan relaxes the small blood vessels of patients with MVA which lends support to the idea that Zibotentan may bring some benefits to patients with MVA. We are interested in re-purposing Zibotentan as a new treatment for patients with MVA and Cambridge is a participating recruitment site for a large trial (the PRIZE study) to look at this. The study will enrich for 'responders' by screening patients with MVA for a gene mutation that increases levels of circulating endothelin. The trial aims to initially invite approx. 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 broaden inclusion by inviting patients with MVA who are screen failures at our site into a sub-study assessing the effect of Zibotentan in patients with different genetic variants in the ET-1 pathway and degrees of microvascular angina quantified by cardiac MRI to assess the therapeutic potential of Zibotentan in other patient groups. Data from this sub-study could justify further analysis of the main study as well as being a genetic repository and bio-resource for future research.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Papworth Hospital NHS Foundation Trust

Criteria

Inclusion Criteria:

1. Age >18 years.

2. Microvascular angina as defined by COVADIS criteria. For the purposes of the trial, this is defined as patients with symptoms of angina or equivalent, absence of epicardial coronary artery stenosis (angiographically >50% stenosis or FFR <0.8) and cardiac MRI evidence of abnormal myocardial perfusion.

3. Able to comply with study procedures.

4. Written informed consent.

Exclusion Criteria:

1. Non-cardiovascular exercise-limiting problem e.g. morbid (or severe) obesity (BMI ≥40.0 kg/m2)

2. Genotype not available

3. 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.

4. 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.

5. Heart failure (New York Heart Association Grade ≥II i.e. mild symptoms and slight limitation during ordinary activity)

6. Recent (<3 months) myocardial infarction

7. A history of epilepsy, other CNS adverse events, neurological symptoms or signs consistent with spinal cord compression or CNS metastases.

8. Moderate or more severe renal impairment (GFR < 45 mL/min)

9. Liver disease with a Child-Pugh score of A (5-6 points) or higher

10. 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).