MICA: A Developmental Trial of Personalised Medicine for Repurposing Zibotentan, a Selective Endothelin A Receptor Blocker, in Microvascular Angina.

Angina is a symptom triggered by a lack of blood supply to the heart. Usually, angina is considered as being due to blockages in the main heart arteries, but angina may also occur due to problems with the small vessels (typically, as thin as a hair). In the UK, angina affects around 2 million people, at least one third of whom may have small vessel problems in the heart (microvascular angina (MVA)). The current medicines are used largely by trial and error since the available drugs were not specifically tested in patients with MVA. Microvascular angina is caused by abnormalities of the small vessels in the heart. The walls of the blood vessels become stiff or thicken and prone to spasm. These problems may limit blood supply to the heart causing anginal chest symptoms during exercise and at other times e.g. cold weather, emotional stress. Physical and psychological symptoms curtail daily activities and reduce quality of life for those affected. Endothelin is a small chemical that circulates in the blood and can accumulate in the blood and blood vessel walls in patients with MVA. Endothelin causes blood vessels to narrow or go into spasm, and thicken in the longer term especially when endothelin levels are increased in the blood. Endothelin works by acting on one of two pathways (A- or B) and it is the 'A' pathway that causes the blood vessel problems in the heart. Zibotentan is an endothelin A blocker. To our knowledge, zibotentan is the most selective blocker of the A pathway with no effects on the B pathway. Zibotentan had been developed as a treatment for cancer but it did not improve survival. Much is known about zibotentan and the safety profile is better than other endothelin blocker drugs. Zibotentan is given as a once daily dose of a single tablet (10 milligrams). Based on previous studies, the safety and potential benefits of zibotentan are well established for the 10 mg dose. Research in our University indicates that zibotentan relaxes the small blood vessels of patients with MVA which lends support to the idea that zibotentan may bring benefits to patients with MVA. What does the study involve? Patients with a diagnosis of MVA will be invited to participate. The eligibility criteria are: age >18 years, angina without blocked heart arteries, NHS test results that indicate a diagnosis of MVA, exercise limitation as revealed by a treadmill test. Patients who have exercise limitation due to non-cardiac health problems would not be eligible to take part. The study will take place in 4 hospitals across the UK. Initially, 356 patients will be invited to take part for a gene test (eligibility criterion), then 144 will then be enrolled into screening (<= 6 weeks), a 3 week 'run-in' phase to become familiar with the study medication, and finally 100 patients will progress into the main study to receive zibotentan or a dummy tablet (placebo). The main study involves two periods of 12 weeks, with zibotentan (10 mg daily) or a matched placebo. Patients and researchers will not know the type of tablet being taken. The hospital will provide a supply of the tablets for the duration of the study. Overall, there will be 5 visits over approximately 34 weeks. A health check will be performed at each visit, including a blood and a urine test, some quality of life questionnaires, and an exercise test. The patient will be guided and supported by trained staff on how to do the exercise test. Feedback from patients indicated an exercise test was preferable to an MRI heart scan, therefore, MRI is entirely optional. The MRI scanner is shaped like a large polo-mint, and by lying inside it, images of the heart and blood flow can be obtained whilst a drug called adenosine is given to relax the blood vessels. The MRI would be performed on 3 occasions. Favourable results in this study will support a 'next stage' grant application for a definitive study involving a longer treatment period eg. 6 - 12 months, and in a larger group of patient.