A Randomised, Double-blind, Placebo-controlled, Cross-over Trial of Zibotentan in Microvascular Angina
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 225
- 试验地点
- 1
- 主要终点
- EFFICACY - Exercise Testing (treadmill exercise time, seconds)
研究概览
简要总结
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).
详细描述
The study design publication is available at https://pubmed.ncbi.nlm.nih.gov/32942043/
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >18 years.
- •Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina.
- •Able to comply with study procedures.
- •Written informed consent.
排除标准
- •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.
- •Non-cardiovascular exercise-limiting problem e.g. morbid (or severe) obesity (BMI ≥40.0 kg/m2)
- •Genotype not available
- •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.
- •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.
- •Heart failure (New York Heart Association Grade ≥II i.e. mild symptoms and slight limitation during ordinary activity)
- •Recent (<3 months) myocardial infarction
- •A history of epilepsy, other CNS adverse events, neurologic symptoms or signs consistent with spinal cord compression or CNS metastases.
- •Moderate or more severe renal impairment (GFR < 45 mL/min)
- •Liver disease with a Child-Pugh score of A (5-6 points) or higher
- •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).
研究组 & 干预措施
Zibotentan
干预措施: Zibotentan (Drug)
Placebo
干预措施: Placebo oral tablet (Drug)
结局指标
主要结局
EFFICACY - Exercise Testing (treadmill exercise time, seconds)
时间窗: 34 weeks
The primary outcome is the treadmill exercise time (TET) measured in seconds using the Full Bruce protocol, a measure of aerobic capacity that reflects disease severity. A within-subject improvement in exercise time (tested at week 10 (baseline), week 22 (crossover) and week 34 (final visit)) of 30 seconds is considered clinically relevant.
次要结局
- EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4)(34 weeks)
- EFFICACY - Exercise Testing (Time (s) to 75% of max age-related heart rate during exercise)(34 weeks)
- EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ)(34 weeks)
- EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM)(34 weeks)
- EFFICACY - Health Status QLQ (EQ5D-5L)(34 weeks)
- FEASIBILITY - Withdrawal Rate(34 weeks)
- SAFETY - SAEs(34 weeks)
- EFFICACY - Exercise Testing (time,sec to 1mm ST-depression)(34 weeks)
- EFFICACY - Exercise Testing (Metabolic equivalent (METs)(34 weeks)
- EFFICACY - Health Status QLQ (Seattle Angina Questionnaire)(34 weeks)
- EFFICACY - Exercise Testing (maximum ST-segment deviation, mV)(34 weeks)
- EFFICACY - Exercise Testing (DUKE Score)(34 weeks)