Back to resultsPrecision Medicine With Zibotentan in Microvascular Angina (PRIZE)
Primary Purpose
Microvascular Angina
Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Zibotentan
Placebo oral tablet
Sponsored by
About this trial
This is an interventional treatment trial for Microvascular Angina focused on measuring Microvascular Angina, Angina, Endothelin, MVA, Impaired Exercise Intolerance
Eligibility Criteria
Inclusion Criteria:
- Age >18 years.
- Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina.
- Able to comply with study procedures.
- Written informed consent.
Exclusion Criteria:
- 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).
Sites / Locations
- NHS Greater Glasgow and Clyde
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Zibotentan
Placebo
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
EFFICACY - Health Status QLQ (Seattle Angina Questionnaire)
Seattle Angina Questionnaire (SAQ) Summary Score and component scores (Angina Limitation, Angina Stability, Angina Frequency, Treatment Satisfaction and Quality of Life) will be recorded at all study visits.
EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ)
Brief Illness Perception Questionnaire (Brief IPQ), a nine-item scale designed to rapidly assess the cognitive and emotional representations of illness taken at all study visits.
EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4)
The Four-Item Patient Health Questionnaire (PHQ-4) for Anxiety and Depression is a validated tool for detecting both anxiety and depressive disorders and will administered at all study visits
EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM)
The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) is a reliable and valid instrument to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction and will administered at all study visits
EFFICACY - Health Status QLQ (EQ5D-5L)
The 5-item EuroQol Group EQ5D-5L is a validated questionnaire comprising mobility, self-care, usual activities, pain/discomfort and anxiety/depression to quantitatively assess patient's self-reported health status and will be administered at each study visit.
FEASIBILITY - Withdrawal Rate
Participant withdrawal rate from study will be measured throughout.
SAFETY - SAEs
Number of Participants With Treatment-Related Adverse Events as Assessed and reported by local study teams throughout trial.
EFFICACY - Exercise Testing (time,sec to 1mm ST-depression)
Within-subject improvements in time (seconds) to 1 mm ST-depression during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
EFFICACY - Exercise Testing (maximum ST-segment deviation, mV)
Within-subject improvements in maximum ST-segment deviation (mV) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
EFFICACY - Exercise Testing (Time (s) to 75% of max age-related heart rate during exercise)
Within-subject improvements in time (seconds) to 75% of max age-related heart rate during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
EFFICACY - Exercise Testing (Metabolic equivalent (METs)
Within-subject improvements in metabolic equivalent (METs) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). The resting metabolic rate is defined as 3.5 ml O2/kg/min (METs).
EFFICACY - Exercise Testing (DUKE Score)
Within-subject improvements in Duke treadmill score (DTS) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). Duke treadmill score is defined as maximum exercise time in minutes - (5 × the maximal net ST-segment deviation in mm during or after exercise) - (4 × the treadmill angina index (where 0 = no angina, 1 = non-limiting angina, 2 = exercise limiting angina).
Full Information
NCT ID
NCT04097314
First Posted
July 5, 2019
Last Updated
August 2, 2023
Sponsor
NHS Greater Glasgow and Clyde
Collaborators
University of Glasgow, King's College London, University of Oxford, Oxford University Hospitals NHS Trust, University of Cambridge, Papworth Hospital NHS Foundation Trust, Blackpool Teaching Hospitals NHS Foundation Trust, Royal Free Hospital NHS Foundation Trust, AstraZeneca UK Ltd, Siemens Healthcare Ltd
1. Study Identification
Unique Protocol Identification Number
NCT04097314
Brief Title
Precision Medicine With Zibotentan in Microvascular Angina
Acronym
PRIZE
Official Title
A Randomised, Double-blind, Placebo-controlled, Cross-over Trial of Zibotentan in Microvascular Angina
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
October 18, 2019 (Actual)
Primary Completion Date
June 8, 2023 (Actual)
Study Completion Date
June 8, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NHS Greater Glasgow and Clyde
Collaborators
University of Glasgow, King's College London, University of Oxford, Oxford University Hospitals NHS Trust, University of Cambridge, Papworth Hospital NHS Foundation Trust, Blackpool Teaching Hospitals NHS Foundation Trust, Royal Free Hospital NHS Foundation Trust, AstraZeneca UK Ltd, Siemens Healthcare Ltd
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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/
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Microvascular Angina
Keywords
Microvascular Angina, Angina, Endothelin, MVA, Impaired Exercise Intolerance
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
225 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Zibotentan
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Zibotentan
Intervention Description
10mg OD Zibotentan
Intervention Type
Drug
Intervention Name(s)
Placebo oral tablet
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
EFFICACY - Exercise Testing (treadmill exercise time, seconds)
Description
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.
Time Frame
34 weeks
Secondary Outcome Measure Information:
Title
EFFICACY - Health Status QLQ (Seattle Angina Questionnaire)
Description
Seattle Angina Questionnaire (SAQ) Summary Score and component scores (Angina Limitation, Angina Stability, Angina Frequency, Treatment Satisfaction and Quality of Life) will be recorded at all study visits.
Time Frame
34 weeks
Title
EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ)
Description
Brief Illness Perception Questionnaire (Brief IPQ), a nine-item scale designed to rapidly assess the cognitive and emotional representations of illness taken at all study visits.
Time Frame
34 weeks
Title
EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4)
Description
The Four-Item Patient Health Questionnaire (PHQ-4) for Anxiety and Depression is a validated tool for detecting both anxiety and depressive disorders and will administered at all study visits
Time Frame
34 weeks
Title
EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM)
Description
The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) is a reliable and valid instrument to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction and will administered at all study visits
Time Frame
34 weeks
Title
EFFICACY - Health Status QLQ (EQ5D-5L)
Description
The 5-item EuroQol Group EQ5D-5L is a validated questionnaire comprising mobility, self-care, usual activities, pain/discomfort and anxiety/depression to quantitatively assess patient's self-reported health status and will be administered at each study visit.
Time Frame
34 weeks
Title
FEASIBILITY - Withdrawal Rate
Description
Participant withdrawal rate from study will be measured throughout.
Time Frame
34 weeks
Title
SAFETY - SAEs
Description
Number of Participants With Treatment-Related Adverse Events as Assessed and reported by local study teams throughout trial.
Time Frame
34 weeks
Title
EFFICACY - Exercise Testing (time,sec to 1mm ST-depression)
Description
Within-subject improvements in time (seconds) to 1 mm ST-depression during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
Time Frame
34 weeks
Title
EFFICACY - Exercise Testing (maximum ST-segment deviation, mV)
Description
Within-subject improvements in maximum ST-segment deviation (mV) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
Time Frame
34 weeks
Title
EFFICACY - Exercise Testing (Time (s) to 75% of max age-related heart rate during exercise)
Description
Within-subject improvements in time (seconds) to 75% of max age-related heart rate during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
Time Frame
34 weeks
Title
EFFICACY - Exercise Testing (Metabolic equivalent (METs)
Description
Within-subject improvements in metabolic equivalent (METs) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). The resting metabolic rate is defined as 3.5 ml O2/kg/min (METs).
Time Frame
34 weeks
Title
EFFICACY - Exercise Testing (DUKE Score)
Description
Within-subject improvements in Duke treadmill score (DTS) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). Duke treadmill score is defined as maximum exercise time in minutes - (5 × the maximal net ST-segment deviation in mm during or after exercise) - (4 × the treadmill angina index (where 0 = no angina, 1 = non-limiting angina, 2 = exercise limiting angina).
Time Frame
34 weeks
Other Pre-specified Outcome Measures:
Title
EFFICACY - Pharmacodynamics (Exploratory)
Description
Blood samples will be obtained at weeks 10, 22 and 34 to measure circulating concentrations of mechanistic biomarkers. These analyses are intended to provide insights into the mechanisms of treatment-related efficacy and safety responses.These measurements will be considered an exploratory endpoint.
Time Frame
34 weeks
Title
EFFICACY - Pharmacokinetics (Exploratory)
Description
Blood samples will be obtained at weeks 10, 22 and 34 to measure steady-state plasma concentrations of zibotentan with a validated assay. These measurements will be considered an exploratory endpoint.
Time Frame
34 weeks
Title
EFFICACY - Angina Diary (Exploratory)
Description
A novel, bespoke questionnaire for the diagnostic classification of patients with ischaemia with non-obstructive coronary artery disease (INOCA) and their treatment response will be assessed as an exploratory outcome. Patients are asked to complete this diary every time they suffer angina symptoms over the course of the trial.
Time Frame
34 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age >18 years.
Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina.
Able to comply with study procedures.
Written informed consent.
Exclusion Criteria:
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).
Facility Information:
Facility Name
NHS Greater Glasgow and Clyde
City
Glasgow
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Precision Medicine With Zibotentan in Microvascular Angina
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