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

MICA：重新利用 Zibotentan（一种选择性内皮素 A 受体阻滞剂）治疗微血管心绞痛的个性化医疗开发试验。

• 批准号: MR/S018905/1
• 负责人: Colin Berry
• 金额: $ 362.45万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS018905%2F1
• 关键词: MICA; Developmental; Trial; Personalised; Medicine

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.

心绞痛是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动脉阻塞，但心绞痛也可能是由于小血管（通常细如头发）的问题而发生的。在英国，心绞痛影响大约200万人，其中至少三分之一的人可能有心脏小血管问题（微血管性心绞痛（MVA））。目前的药物在很大程度上是通过试验和错误来使用的，因为现有的药物没有专门在MVA患者中进行测试。微血管性心绞痛是由心脏中的小血管异常引起的。血管壁变得僵硬或松弛，易于痉挛。这些问题可能会限制心脏的血液供应，导致心绞痛的胸部症状，在运动期间和其他时间，例如寒冷的天气，情绪紧张。身体和心理症状减少日常活动，降低患者的生活质量。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中积累。内皮素导致血管狭窄或痉挛，并在长期内尤其是当血液中内皮素水平升高时发生痉挛。内皮素通过作用于两条通路（A-或B）中的一条而起作用，并且正是“A”通路导致心脏中的血管问题。Zibotentan是一种内皮素A阻滞剂。据我们所知，zibotentan是A途径的最具选择性的阻断剂，对B途径没有影响。Zibotentan被开发用于治疗癌症，但它并没有改善生存率。关于Zibotentan的了解很多，其安全性优于其他内皮素阻滞剂药物。Zibotentan是一种每日一次的单剂量片剂（10毫克）。根据先前的研究，10 mg剂量的齐博腾坦的安全性和潜在获益已得到充分证实。我们大学的研究表明，zibotentan放松了MVA患者的小血管，这支持了zibotentan可能为MVA患者带来益处的想法。这项研究涉及哪些内容？将邀请诊断为MVA的患者参加。资格标准为：年龄>18岁，心绞痛而无心脏动脉阻塞，NHS测试结果表明诊断为MVA，跑步机测试显示运动受限。由于非心脏健康问题而导致运动受限的患者不符合参加研究的资格。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（合格标准），然后144名患者将被纳入筛选（<= 6周），这是一个为期3周的“导入”阶段，以熟悉研究药物，最后100名患者将进入主研究，接受zibotentan或模拟片剂（安慰剂）。主要研究包括两个为期12周的阶段，使用zibotentan（每天10 mg）或匹配的安慰剂。患者和研究人员将不知道正在服用的片剂类型。医院将在研究期间提供片剂。总体而言，将在约34周内进行5次访视。每次访视时将进行健康检查，包括血液和尿液检查、一些生活质量问卷和运动试验。患者将由经过培训的工作人员指导和支持如何进行运动试验。患者的反馈表明，运动试验优于MRI心脏扫描，因此，MRI是完全可选的。MRI扫描仪的形状像一个大的波罗薄荷，躺在里面，可以获得心脏和血流的图像，同时给予一种叫做腺苷的药物来放松血管。MRI将进行3次。这项研究的有利结果将支持一项涉及更长治疗期的确定性研究的“下一阶段”资助申请，例如。6 - 12个月，并且在更大的患者组中。

项目成果

Strengths and limitations of meta-analyses.

荟萃分析的优点和局限性。

• DOI: 10.1093/eurheartj/ehab682
• 发表时间: 2022
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Berry C

Mechanistic Study of the Effect of Endothelin SNPs in Microvascular Angina - protocol of the PRIZE Endothelin Sub-Study

内皮素 SNP 在微血管心绞痛中作用的机制研究 - PRIZE 内皮素子研究方案

• DOI: 10.17863/cam.80960
• 发表时间: 2022
• 作者: Abraham G

FAVOR III China: quantitative flow ratio-guided coronary intervention in practice.

FAVOR III 中国：定量血流比引导冠状动脉介入治疗的实践。

• DOI: 10.1093/cvr/cvac109
• 发表时间: 2022
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Ang D

Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19.

• DOI: 10.1016/j.yjmcc.2022.03.007
• 发表时间: 2022-06
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Abraham GR;Kuc RE;Althage M;Greasley PJ;Ambery P;Maguire JJ;Wilkinson IB;Hoole SP;Cheriyan J;Davenport AP
• 通讯作者: Davenport AP

Personalizing the Competing Risks for Thrombotic and Bleeding Events in Ischemia With Nonobstructed Coronary Arteries.

个性化无阻塞冠状动脉缺血中血栓和出血事件的竞争风险。

• DOI: 10.1016/j.jcin.2021.12.010
• 发表时间: 2022
• 期刊: JACC. Cardiovascular interventions
• 作者: Berry C