Microvascular AnginaNCT04508998
PRIZE ET Sub-Study
A study testing Blood tests including genotyping and Exercise Tolerance Test in people with Microvascular Angina, run by Papworth Hospital NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
Microvascular angina (MVA) is caused by abnormalities of the small blood vessels in the heart. Endothelin-1 (ET-1) is a chemical messenger that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken over a long period, especially as levels of ET-1 increase. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Microvascular Angina
- What is being tested?
- Blood tests including genotyping and Exercise Tolerance Test
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 14 May 2021to 13 Aug 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age >18 years.
- Probable or definite Microvascular Angina as defined in COVADIS criteria:
- Clinical symptoms of angina
- No obstructive coronary artery disease
- Objective evidence of myocardial ischemia
- Evidence of impaired coronary microvascular function (Optional)
Show all 9Show fewer
- Able to comply with study procedures.
- Screen failure for the main PRIZE study
- Written informed consent.
Who cannot join
- 1. Lack of informed consent for the PRIZE ET Sub-study
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Papworth Hospital NHS Foundation Trust
Cambridge, CB2 0AY
About this study
Official title: Mechanistic Study of the Effect of ET-1 SNPs in Coronary Microvascular Disease
Microvascular angina (MVA) is caused by abnormalities of the small blood vessels in the heart. Endothelin-1 (ET-1) is a chemical messenger that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken over a long period, especially as levels of ET-1 increase. As a result, patients experience pain, psychological distress and limitation of their daily activities.
Cambridge is a participating recruitment site for a large randomised, double blinded, placebo controlled crossover trial (the PRIZE study: NCT04097314) investigating Zibotentan as a new drug treatment for patients with MVA using a 'precision medicine' approach. Zibotentan is a drug originally developed by Astra Zeneca for prostate cancer but prior research has shown that it acts to relax the small blood vessels of patients with MVA, highlighting its potential as a novel therapy for this patient group. The PRIZE study population will be enriched for 'responders' to the drug by screening patients with MVA for a gene mutation known to increase levels of circulating endothelin. The trial aims to initially invite approximately 356 participants for genetic testing but only 100 participants will go forward into the main study, with approximately 2/3rd being screen failures.
In our sub-study, we will invite patients with MVA who are screen failures at our site for further blood tests looking for other genetic variants in the ET-1 signalling pathway and examine how this correlates with the severity of microvascular angina quantified by cardiac MRI and clinical assessments. Data from this sub-study would provide a bio-resource for further analysis of the main PRIZE trial to identify other patients that would benefit from Zibotentan.
Read the detailed description
Patients with microvascular angina (MVA) are under-diagnosed and have limited therapeutic options available to them. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the small vessel obstruction that causes MVA. The PRIZE trial will apply a precision medicine approach to assess the therapeutic effect of Zibotentan, an ET-1 antagonist (ETA) selective for the ETA receptor in patients who are high ET-1 expressors (possessing the PHACTR1 minor GG allele single nucleotide polymorphism - SNP). Unfortunately, the incidence of this SNP occurs in only a third of the population, resulting in a high screen-failure rate.
In the proposed sub-study, we aim to recruit patients with MVA but without the minor GG allele SNP to potentially identify other potential 'responders' to Zibotentan. In an observational mechanistic study, we will perform baseline genotyping for other genetic variants in the ET-1 pathway as well as phenotyping patients by quantification of microvascular disease from retrospective analysis of cardiac MRI data. Patients will also complete angina and quality of life questionnaires and perform an exercise stress test to determine maximal exercise distance. Information from this sub-study will provide a genotype bio-resource that could identify novel SNPs for the pathogenesis of MVA that could be validated in the UK biobank. This may indicate other ETA receptor antagonist super-responders, justifying treatment with Zibotentan and enabling more patients with MVA to potentially benefit from this promising drug.
- Conditions
- Microvascular Angina
- Being tested
- Blood tests including genotyping, Exercise Tolerance Test
- Keywords
- angina, endothelin receptor antagonist, zibotentan
- Medical subject headings
- Microvascular Angina, Angina Pectoris
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood tests including genotypingDiagnostic test
Blood tests for alternative SNPs altering levels of ET-A receptor expression; blood will be further analysed for endothelin receptor mRNA and other plasma peptides important in the endothelin signalling pathway
Exercise Tolerance TestDiagnostic test
Treadmill exercise test using the Bruce protocol
| Study group | Role | What they receive |
|---|---|---|
| Patients with microvascular angina | Experimental | Patients with clinical features of microvascular angina screened for the main PRIZE trial however not possessing the PHACTR1 GG minor allele single nucleotide polymorphism Receives: Diagnostic Test: Blood tests including genotyping; Diagnostic Test: Exercise Tolerance Test |
What is being measured
The primary outcome is the main question the study is designed to answer.
Correlation of ET-A SNPs with ET-A expression in blood by qPCR, levels of endothelin related plasma peptides and clinical data (exercise duration and microvascular disease measured by quantitative perfusion on Cardiac MRI)
Measurement of molecules associated with the endothelin signalling pathway in patients with different SNPs for the ET-A receptor will be compared with phenotypic characteristics of the patients, specifically exercise tolerance and by retrospective analysis of the patient's cardiac MRI using quantitative measures of myocardial blood flow.
Measured: correlation will be assessed at baseline at the start of the trial (time point 0)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2020
- Study start14 May 2021
- Primary completion13 Aug 2022
- Study completion13 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Microvascular AnginaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- Papworth Hospital NHS Foundation Trust
- Sponsor type
- Other government
- Collaborators
- NHS Greater Glasgow and Clyde
- Responsible party
- Sponsor
- Investigators
- Stephen Hoole, Principal investigator, Royal Papworth NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04508998
- Sponsor's protocol ID
- P02664
- Status last verified
- Apr 2023
- First submitted
- 21 Jun 2020
- Last updated
- 4 Apr 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be entered on electronic clinical record forms inputed on the Open Clinica eCRF platform with password protected access for researchers and for quality assurance personnel only.
Publications
Abraham GR, Morrow AJ, Oliveira J, Weir-McCall JR, Davenport EE, Berry C, Davenport AP, Hoole SP. Mechanistic study of the effect of Endothelin SNPs in microvascular angina - Protocol of the PRIZE Endothelin Sub-Study. Int J Cardiol Heart Vasc. 2022 Feb 25;39:100980. doi: 10.1016/j.ijcha.2022.100980. eCollection 2022 Apr.
PubMed 35242999
Study at a glance
From the registry record, last updated by the sponsor on 4 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanistic Study of the Effect of ET-1 SNPs in Coronary Microvascular Disease
- ClinicalTrials.gov ID
- NCT04508998
- Acronym / sponsor ID
- P02664
- Conditions
- Microvascular Angina
- Keywords
- angina, endothelin receptor antagonist, zibotentan
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- Papworth Hospital NHS Foundation TrustOther government
- Collaborators
- NHS Greater Glasgow and Clyde
- Study start
- 14 May 2021 (actual)
- Primary completion
- 13 Aug 2022 (actual)
- Study completion
- 13 Aug 2022 (actual)
- First posted
- 11 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Microvascular angina (MVA) is caused by abnormalities of the small blood vessels in the heart. Endothelin-1 (ET-1) is a chemical messenger that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken over a long period, especially as levels of ET-1 increase. As a result, patients experience pain, psychological distress and limitation of their daily activities.
Cambridge is a participating recruitment site for a large randomised, double blinded, placebo controlled crossover trial (the PRIZE study: NCT04097314) investigating Zibotentan as a new drug treatment for patients with MVA using a 'precision medicine' approach. Zibotentan is a drug originally developed by Astra Zeneca for prostate cancer but prior research has shown that it acts to relax the small blood vessels of patients with MVA, highlighting its potential as a novel therapy for this patient group. The PRIZE study population will be enriched for 'responders' to the drug by screening patients with MVA for a gene mutation known to increase levels of circulating endothelin. The trial aims to initially invite approximately 356 participants for genetic testing but only 100 participants will go forward into the main study, with approximately 2/3rd being screen failures.
In our sub-study, we will invite patients with MVA who are screen failures at our site for further blood tests looking for other genetic variants in the ET-1 signalling pathway and examine how this correlates with the severity of microvascular angina quantified by cardiac MRI and clinical assessments. Data from this sub-study would provide a bio-resource for further analysis of the main PRIZE trial to identify other patients that would benefit from Zibotentan.
Detailed description
Patients with microvascular angina (MVA) are under-diagnosed and have limited therapeutic options available to them. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the small vessel obstruction that causes MVA. The PRIZE trial will apply a precision medicine approach to assess the therapeutic effect of Zibotentan, an ET-1 antagonist (ETA) selective for the ETA receptor in patients who are high ET-1 expressors (possessing the PHACTR1 minor GG allele single nucleotide polymorphism - SNP). Unfortunately, the incidence of this SNP occurs in only a third of the population, resulting in a high screen-failure rate.
In the proposed sub-study, we aim to recruit patients with MVA but without the minor GG allele SNP to potentially identify other potential 'responders' to Zibotentan. In an observational mechanistic study, we will perform baseline genotyping for other genetic variants in the ET-1 pathway as well as phenotyping patients by quantification of microvascular disease from retrospective analysis of cardiac MRI data. Patients will also complete angina and quality of life questionnaires and perform an exercise stress test to determine maximal exercise distance. Information from this sub-study will provide a genotype bio-resource that could identify novel SNPs for the pathogenesis of MVA that could be validated in the UK biobank. This may indicate other ETA receptor antagonist super-responders, justifying treatment with Zibotentan and enabling more patients with MVA to potentially benefit from this promising drug.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with microvascular angina | Experimental | Diagnostic Test: Blood tests including genotyping, Diagnostic Test: Exercise Tolerance TestPatients with clinical features of microvascular angina screened for the main PRIZE trial however not possessing the PHACTR1 GG minor allele single nucleotide polymorphism |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Age >18 years.
- Probable or definite Microvascular Angina as defined in COVADIS criteria:
- Able to comply with study procedures.
- Screen failure for the main PRIZE study
- Written informed consent.
Key exclusion criteria (1 listed)
- 1. Lack of informed consent for the PRIZE ET Sub-study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Blood tests including genotypingBlood tests for alternative SNPs altering levels of ET-A receptor expression; blood will be further analysed for endothelin receptor mRNA and other plasma peptides important in the endothelin signalling pathway | Diagnostic test | Patients with microvascular angina |
| Exercise Tolerance TestTreadmill exercise test using the Bruce protocol | Diagnostic test | Patients with microvascular angina |
Primary outcome
Correlation of ET-A SNPs with ET-A expression in blood by qPCR, levels of endothelin related plasma peptides and clinical data (exercise duration and microvascular disease measured by quantitative perfusion on Cardiac MRI)
Time frame: correlation will be assessed at baseline at the start of the trial (time point 0)
Measurement of molecules associated with the endothelin signalling pathway in patients with different SNPs for the ET-A receptor will be compared with phenotypic characteristics of the patients, specifically exercise tolerance and by retrospective analysis of the patient's cardiac MRI using quantitative measures of myocardial blood flow.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Apr 2023.
- Background: PubMed 35242999Abraham GR, Morrow AJ, Oliveira J, Weir-McCall JR, Davenport EE, Berry C, Davenport AP, Hoole SP. Mechanistic study of the effect of Endothelin SNPs in microvascular angina - Protocol of the PRIZE Endothelin Sub-Study. Int J Cardiol Heart Vasc. 2022 Feb 25;39:100980. doi: 10.1016/j.ijcha.2022.100980. eCollection 2022 Apr.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Data will be entered on electronic clinical record forms inputed on the Open Clinica eCRF platform with password protected access for researchers and for quality assurance personnel only.
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Microvascular Angina
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stephen Hoole principal investigator
Royal Papworth NHS Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Blood tests including genotyping and Exercise Tolerance Test in people with Microvascular Angina, run by Papworth Hospital NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Correlation of ET-A SNPs with ET-A expression in blood by qPCR, levels of endothelin related plasma peptides and clinical data (exercise duration and microvascular disease measured by quantitative perfusion on Cardiac MRI) (time frame: correlation will be assessed at baseline at the start of the trial (time point 0)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04508998, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2023.