Clinical trial NCT04097314: Precision Medicine With Zibotentan in Microvascular Angina
Official title: A Randomised, Double-blind, Placebo-controlled, Cross-over Trial of Zibotentan in Microvascular Angina
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Microvascular Angina
Keywords: Microvascular Angina
Angina
Endothelin
MVA
Impaired Exercise Intolerance
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Glasgow
name: King's College London
name: University of Oxford
name: Oxford University Hospitals NHS Trust
name: University of Cambridge
name: Papworth Hospital NHS Foundation Trust
name: Blackpool Teaching Hospitals NHS Foundation Trust
name: Royal Free Hospital NHS Foundation Trust
name: AstraZeneca
name: Siemens Healthcare Ltd
First posted: 2019-09-20
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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).

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

Eligibility criteria: 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).

Primary outcomes:
measure: EFFICACY - Exercise Testing (treadmill exercise time, seconds)
timeFrame: 34 weeks
Secondary outcomes:
measure: EFFICACY - Health Status QLQ (Seattle Angina Questionnaire)
timeFrame: 34 weeks
measure: EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ)
timeFrame: 34 weeks
measure: EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4)
timeFrame: 34 weeks
measure: EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM)
timeFrame: 34 weeks
measure: EFFICACY - Health Status QLQ (EQ5D-5L)
timeFrame: 34 weeks
measure: FEASIBILITY - Withdrawal Rate
timeFrame: 34 weeks
measure: SAFETY - SAEs
timeFrame: 34 weeks
measure: EFFICACY - Exercise Testing (time,sec to 1mm ST-depression)
timeFrame: 34 weeks
measure: EFFICACY - Exercise Testing (maximum ST-segment deviation, mV)
timeFrame: 34 weeks
measure: EFFICACY - Exercise Testing (Time (s) to 75% of max age-related heart rate during exercise)
timeFrame: 34 weeks
measure: EFFICACY - Exercise Testing (Metabolic equivalent (METs)
timeFrame: 34 weeks
measure: EFFICACY - Exercise Testing (DUKE Score)
timeFrame: 34 weeks
Other outcomes:
measure: EFFICACY - Pharmacodynamics (Exploratory)
timeFrame: 34 weeks
measure: EFFICACY - Pharmacokinetics (Exploratory)
timeFrame: 34 weeks
measure: EFFICACY - Angina Diary (Exploratory)
timeFrame: 34 weeks
Locations:
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
Study officials:
References: