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

心绞痛是一种由心脏供血不足引起的症状。通常，心绞痛被认为是由于心脏主要动脉阻塞引起的，但心绞痛也可能是由于小血管（通常像头发一样细）的问题引起的。在英国，心绞痛影响了大约200万人，其中至少三分之一的人可能在心脏有小血管问题（微血管心绞痛（MVA））。目前的药物主要是通过试验和错误来使用的，因为现有的药物没有在MVA患者中进行专门的测试。微血管性心绞痛是由心脏小血管异常引起的。血管壁变得僵硬或变厚，容易痉挛。这些问题可能会限制心脏的血液供应，在运动时或在其他时间（如寒冷天气、情绪紧张）引起心绞痛胸症状。身体和心理症状限制了患者的日常活动，降低了患者的生活质量。内皮素是一种在血液中循环的小化学物质，可以在MVA患者的血液和血管壁上积聚。内皮素导致血管变窄或痉挛，并在较长时间内增厚，特别是当血液中的内皮素水平升高时。内皮素通过作用于两种途径（A-或B）之一起作用，而导致心脏血管问题的是A途径。Zibotentan是一种内皮素A阻滞剂。据我们所知，zibotentan是A途径选择性最强的阻滞剂，对B途径没有影响。Zibotentan曾被开发用于治疗癌症，但它并没有提高生存率。zibotentan的安全性比其他内皮素阻滞剂药物要好。Zibotentan每天服用一次片剂（10毫克）。根据以往的研究，10毫克剂量的zibotentan的安全性和潜在益处已经得到了很好的证实。我们大学的研究表明滋他坦可以使MVA患者的小血管松弛，这支持了滋他坦可能对MVA患者有益的观点。这项研究包括什么内容？诊断为MVA的患者将被邀请参加。入选标准为：年龄bb0 - 18岁，心绞痛无心脏动脉阻塞，NHS检查结果提示MVA诊断，跑步机试验显示运动受限。由于非心脏健康问题而限制运动的患者将没有资格参加。这项研究将在英国的4家医院进行。最初，356名患者将被邀请参加基因测试（资格标准），然后144名患者将被纳入筛选（<= 6周），这是一个为期3周的“磨合”阶段，以熟悉研究药物，最后100名患者将进入主要研究，接受zibotentan或假片（安慰剂）。主要研究包括两个为期12周的阶段，使用zibotentan（每天10毫克）或相匹配的安慰剂。患者和研究人员将不知道所服用的药片的类型。医院将在研究期间提供药片的供应。总的来说，将在大约34周内进行5次访问。每次就诊时都会进行健康检查，包括血液和尿液检查、一些生活质量问卷调查和运动测试。患者将在训练有素的工作人员的指导和支持下进行运动测试。患者的反馈表明，运动测试比核磁共振心脏扫描更可取，因此，核磁共振完全是可选的。核磁共振成像扫描仪的形状像一个大的薄荷，躺在里面，心脏和血液流动的图像可以获得，同时给一种叫做腺苷的药物来放松血管。MRI检查共3次。这项研究的有利结果将支持“下一阶段”的拨款申请，以进行一项涉及更长的治疗期的确定研究。6 - 12个月，在更大的患者群体中。

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.