Microvascular angina (MVA) is caused by abnormalities of the small vessels in the heart. Endothelin is a small chemical 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 endothelin increase. As a result, patients experience pain, psychological burden and an inability to carry out 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. This trial therefore proposes to look into re-purposing zibotentan as a new treatment for patients with MVA. The primary objective is to assess the effect of add-on treatment with Zibotentan to treadmill exercise times in adult patients with MVA and impaired exercise intolerance. Zibotentan could provide a new treatment pathway for patients, as well as be made available to the NHS at substantially lower cost than the currently used medications.

The trial aims to initially invite approx. 356 participants for genetic testing. A minimum of 100 participants will go forward into the main study, receiving either 10mg zibotentan or a dummy matched tablet (placebo) daily over two 12 weeks periods of each, completing their final visit at week 34. The study assessments will involve a health check at each visit, including information on the patient's wellbeing, blood tests, some quality of life questionnaires, and an exercise test. Participants will also have the option to consent to additional sub-study cardiovascular MRI scanning. Finally, participants will be invited to provide consent for long-term follow-up (maximum 20 years) of their electronic medical records (no additional patient contact).

The study design publication is available at https://pubmed.ncbi.nlm.nih.gov/32942043/

Inclusion Criteria:

1. Age >18 years.
2. Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina.
3. Able to comply with study procedures.
4. Written informed consent.

Exclusion Criteria:

1. Exercise tolerance >540 seconds in men and >430 seconds in women (i.e. actual exercise duration (s) achieved on the Bruce protocol commensurate with predicted), or, lack of anginal symptoms and/or ST-segment depression (0.1 mV) limiting exercise.
2. Non-cardiovascular exercise-limiting problem e.g. morbid (or severe) obesity (BMI ≥40.0 kg/m2)
3. Genotype not available
4. Women who are pregnant, breast-feeding or of child-bearing potential (WoCBP) without a negative pregnancy test and who are unwilling or unable to follow the reproductive restrictions and use highly effective contraception as defined in Appendix 3 of the protocol for the duration of the study treatment and 30 days after last dose of study drug.
5. 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.
6. Heart failure (New York Heart Association Grade ≥II i.e. mild symptoms and slight limitation during ordinary activity)
7. Recent (<3 months) myocardial infarction
8. A history of epilepsy, other CNS adverse events, neurologic symptoms or signs consistent with spinal cord compression or CNS metastases.
9. Moderate or more severe renal impairment (GFR < 45 mL/min)
10. Liver disease with a Child-Pugh score of A (5-6 points) or higher
11. 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).