Precision Medicine With Zibotentan in Microvascular Angina

NCT04097314 | Completed Phase 2 DMC

• 1 other identifier: GN18CA068
• Study Type: interventional
• Target: 225
• Locations: 1 country
• Sites: 1

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).

Conditions

Microvascular Angina

Keywords

Microvascular Angina; Angina; Endothelin; MVA; Impaired Exercise Intolerance

Outcome Measures

Primary Outcomes (1)

• EFFICACY - Exercise Testing (treadmill exercise time, seconds)

  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.

  34 weeks

Secondary Outcomes (12)

• EFFICACY - Health Status QLQ (Seattle Angina Questionnaire)

  34 weeks

• EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ)

  34 weeks

• EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4)

  34 weeks

• EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM)

  34 weeks

• EFFICACY - Health Status QLQ (EQ5D-5L)

  34 weeks

Other Outcomes (3)

• EFFICACY - Pharmacodynamics (Exploratory)

  34 weeks

• EFFICACY - Pharmacokinetics (Exploratory)

  34 weeks

• EFFICACY - Angina Diary (Exploratory)

  34 weeks

Study Arms (2)

Zibotentan

EXPERIMENTAL

Drug: Zibotentan

Placebo

PLACEBO COMPARATOR

Drug: Placebo oral tablet

Interventions

Zibotentan DRUG

10mg OD Zibotentan

Zibotentan

Placebo oral tablet DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>18 years.
• Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina.
• Able to comply with study procedures.
• Written informed consent.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Blackpool Teaching Hospitals NHS Foundation Trust: collaborator
• NHS Greater Glasgow and Clyde: lead
• University of Glasgow: collaborator
• King's College London: collaborator
• University of Oxford: collaborator
• Oxford University Hospitals NHS Trust: collaborator
• University of Cambridge: collaborator
• Papworth Hospital NHS Foundation Trust: collaborator
• Royal Free Hospital NHS Foundation Trust: collaborator
• AstraZeneca: collaborator
• Siemens Healthcare Ltd: collaborator

Study Sites (1)

NHS Greater Glasgow and Clyde

Glasgow, United Kingdom

Location

Related Publications (1)

• Morrow A, Young R, Abraham GR, Hoole S, Greenwood JP, Arnold JR, El Shibly M, Shanmuganathan M, Ferreira V, Rakhit R, Galasko G, Sinha A, Perera D, Al-Lamee R, Spyridopoulos I, Kotecha A, Clesham G, Ford TJ, Davenport A, Padmanabhan S, Jolly L, Kellman P, Kaski JC, Weir RA, Sattar N, Kennedy J, Macfarlane PW, Welsh P, McConnachie A, Berry C; PRIZE Study Group. Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial. Circulation. 2024 Nov 19;150(21):1671-1683. doi: 10.1161/CIRCULATIONAHA.124.069901. Epub 2024 Sep 1.

  PMID: 39217504 DERIVED

MeSH Terms

Conditions

Microvascular Angina; Angina Pectoris

Interventions

ZD4054

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Chest Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 5, 2019
• First Posted: September 20, 2019
• Study Start: October 18, 2019
• Primary Completion: June 8, 2023
• Study Completion: June 8, 2023
• Last Updated: August 4, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)