Microvascular Angina and impaired exercise intolerance. MedDRA version: 20.0 Level: LLT Classification code 10065566 Term: Microvascular angina System Organ Class: 100000004849
Conditions
Interventions
Product Name: Zibotentan
Product Code: ZD4054
Pharmaceutical Form: Tablet
INN or Proposed INN: Zibotentan
CAS Number: 186497-07-4
Current Sponsor code: Not applicable
Other descriptive name: Not appli
Sponsors
NHS Greater Glasgow & Clyde
University of Glasgow
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age =>18 years. 2. Microvascular angina1. 3. Able to comply with study procedures. 4. Written informed consent. FOR OPTIONAL MRI SUB-STUDY 1. Participation in the main study. 2. Able to comply with the sub-study procedures 3. Written informed consent. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 178 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 178
Exclusion criteria
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. Endothelin 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 defined in section 8.10 (of the study protocol) and use highly effective contraception as defined in Appendix 3 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 [41] 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). FOR OPTIONAL MRI SUB-STUDY 1. Implantable cardiac device i.e. pacemaker, implantable defibrillator. 2. Contra-indication to intravenous adenosine, i.e. asthma; chronic obstructive lung disease; decompensated heart failure; long QT syndrome; second- or third-degree AV block and sick sinus syndrome; severe hypotension. 3. Contra-indication to contrast media
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to assess the effect of add-on treatment with zibotentan on treadmill exercise time based on a Bruce protocol exercise test in patients with microvascular angina and impaired exercise intolerance. ;Secondary Objective: To assess the effects of add-on treatment with zibotentan on other measures of exercise performance, anginal symptoms, and quality of life; To assess whether the effects of add-on treatment with zibotentan on exercise test performance varies by genotype for the endothelin-1 gene SNP regulator; To assess the safety of add-on treatment with zibotentan; To assess the effects of add-on treatment with zibotentan on mechanistic biomarkers, and their association with treatment response/discontinuation ;Primary end point(s): The primary outcome measure will be subject change in exercise duration(s) on the full Bruce protocol at visits 3 and 5;Timepoint(s) of evaluation of this end point: All of the analyses will be carried out according to a detailed Statistical Analysis Plan, to be written and approved prior to database lock and unblinding of treatment allocations, according to Glasgow Clinical Trials Unit (CTU) Standard Operating Procedures. An analysis by genotype will be prioritised. The primary outcome will be analysed in the following sub-groups. Categorical variables: - genotype, sex, history of vasospastic angina. Continuously distributed variables (by thirds of the baseline distribution): age, eGFR, BMI, systolic blood pressure. Results will be presented within each sub-group along with a test for treatment by sub-group interaction. No interim analyses are planned. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): EFFICACY AND MECHANISTIC EXERCISE TEST • Time (s) to 1 mm ST-depression, • Maximum ST-segment deviation (mV), • Time (s) to 75% of max age-related heart rate during exercise, • Metabolic equivalent (METs) (O2/kg/min), • The DUKE Score. HEALTH STATUS • Seattle Angina Questionnaire (SAQ) summary score • SAQ component scores including physical limitation, angina stability & frequency • Illness perception (Brief IPQ), • Anxiety/depression (PHQ4), • Treatment satisfaction (TSQM) FEASIBILITY Withdrawal rate SAFETY Serious adverse events (SAE). ;Timepoint(s) of evaluation of this end point: All of the analyses will be carried out according to a detailed Statistical Analysis Plan, to be written and approved prior to database lock and unblinding of treatment allocations, according to Glasgow Clinical Trials Unit (CTU) Standard Operating Procedures. An analysis by genotype will be prioritised. Serious adverse events will be tabulated by system organ class and preferred term. No interim analyses are planned. | — |
Countries
United Kingdom
Contacts
Public ContactDr Maureen Travers
NHS Greater Glasgow & Clyde
Outcome results
None listed