Refractory AnginaPhase 2/3ARAMISNCT04368819
Allopurinol in Patients With Refractory Angina to Improve Ischemic Symptoms
A Phase 2/3 study testing Allopurinol 300 MG in people with Refractory Angina, run by Ministry of Health, Brazil at 1 site in Brazil.
Trial summary
Despite numerous advances in medical treatment and revascularization procedures for the treatment of patients with stable angina, debilitating symptoms that are unresponsive to conventional therapy may occur in patients unsuitable for revascularization, a condition known as refractory angina. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Refractory Angina
- What is being tested?
- Allopurinol 300 MG
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteBrazil
- Study dates
- 3 Mar 2021to 31 Dec 2021
- Phase
- Phase 2/3
- 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
- Clinical diagnosis of stable angina in functional class (CCS) ≥ 2 for at least three months in patients taking maximally tolerated doses of at least three classes of antianginal agents
- Documentation of myocardial ischemia by any provocative functional test (exercise test, stress echocardiogram, myocardial perfusion scintigraphy or cardiac resonance)
- Signature of the Informed Consent Form
Who cannot join
- Left ventricular dysfunction defined by LVEF < 30% on transthoracic echocardiogram
- Significant concomitant valve disease
- Chronic renal failure stage 4 or 5 (GFR < 30mL/min/1.73m2 calculated by the MDRD equation
- Significant liver dysfunction (Child-Pugh class C) or MELD value ≥ 15 calculated from creatinine, total bilirubin, and INR values
- Current use of warfarin
- Prior use of allopurinol within three months of randomization
- Pregnant and lactating women
Trial locations and contacts
1 site in 1 country.
Brazil1 site, 1 recruiting
- Recruiting
Heart Institute
São Paulo, São Paulo, 05403-000
Luis Henrique W Gowdak, MD, PhD
About this study
Official title: A Single-center, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Allopurinol in Improving Ischemic Symptoms in Patients With Refractory Angina.
Despite numerous advances in medical treatment and revascularization procedures for the treatment of patients with stable angina, debilitating symptoms that are unresponsive to conventional therapy may occur in patients unsuitable for revascularization, a condition known as refractory angina. Allopurinol, a methylxanthine oxidase inhibitor, is widely used in the treatment of gout and asymptomatic hyperuricemia. On the other hand, the anti-ischemic effects of allopurinol have been the subject of increasing interest. Therefore, the investigators will study the safety and efficacy of allopurinol in alleviating ischemic symptoms in patients with refractory angina already on optimal medical therapy.
Read the detailed description
One of the most common clinical presentations associated with coronary artery disease (CAD) is stable angina, which can be translated clinically into chest discomfort (or equivalent) evoked by different levels of physical activity depending on the extent of the disease. In the United States, it is estimated that 16.5 million individuals over 20 years of age have chronic ischemic heart disease, of which 3.4 million live with the diagnosis of angina pectoris. Refractory angina is a clinical condition characterized by the presence of debilitating symptoms secondary to CAD lasting more than three months in which the symptoms are attributed to objectively documented ischemia and not controlled with the combination of conventional antianginal agents and myocardial revascularization procedures. The estimated annual incidence of patients with refractory angina is between 50,000 and 200,000 new cases in the United States.
Allopurinol, a methylxanthine oxidase inhibitor, is widely used in the treatment of gout and asymptomatic hyperuricemia. The therapeutic potential of allopurinol in patients with cardiovascular disease has been the subject of increasing interest. In patients with CAD, the first study tested the role of allopurinol in improving exercise tolerance in 65 patients with stable angina documented by angiography and positive stress test for myocardial ischemia. After only six weeks of treatment, patients who received allopurinol showed a statistically significant increase in ergometry parameters, including time for ST-segment depression, total exercise time, and time until the onset of angina. There were no reports of adverse events. Considerable decrease in inflammatory markers and oxidative stress indicators has been demonstrated in patients with acute myocardial infarction receiving allopurinol versus placebo with a significant reduction in the risk of cardiovascular events in 2 years (10% vs. 30%, respectively). Therefore, the investigators will test the hypothesis that the use of allopurinol increases exercise tolerance and reduces angina attacks compared to placebo after 16 weeks of follow-up in patients with refractory angina.
Patients will be randomly selected to receive a placebo or allopurinol (600mg od) for 16 weeks. At baseline and after 16 weeks of treatment, exercise tolerance will be assessed through the cardiopulmonary exercising test, and myocardial ischemia will be determined using an exercise echocardiogram protocol. Biomarkers of oxidative stress will be measured in the blood and urine; endothelial-dependent vasodilation will be assessed using the reactive hyperemia protocol at the brachial artery.
For the sample size calculation, the investigators chose the primary outcome as "total exercise time (TTE) after intervention" based on the study by Noman et al. (Lancet 2010;375:2161-7). Thus, assuming that μ1 (allopurinol) = 396sec, μ2 (placebo) = 319sec and σ = 63sec, the investigators concluded that to be able to detect a difference between groups with 95% confidence (1-alfa) and 90% power (1-beta), 17 patients are needed in each study group. If the investigators consider a screen failure rate at 20%, a total of 40 patients will be needed, randomized 1:1.
- Conditions
- Refractory Angina
- Being tested
- Allopurinol 300 MG, Placebo oral tablet
- Keywords
- angina, coronary artery disease, myocardial ischemia, treatment, allopurinol, cardiopulmonary exercising test, oxidative stress, stress echocardiogram
- Medical subject headings
- Angina Pectoris, Coronary Artery Disease, Myocardial Ischemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Allopurinol 300 MGDrug
Also called Zyloric
Allopurinol 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks
Placebo oral tabletDrug
Also called Placebo
Placebo 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| Allopurinol | Active comparator | Allopurinol 300mg P.O. once daily for four weeks followed by allopurinol 300mg P.O. twice daily for 12 weeks. Receives: Drug: Allopurinol 300 MG |
| Placebo | Placebo comparator | Placebo pills indistinguishable from the active comparator given P.O. once daily for four weeks, followed by twice daily for 12 weeks. Receives: Drug: Placebo oral tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increase in total exercise time (seconds) assessed by CPET
Total exercise duration during a maximal, symptom-limited cardiopulmonary exercise testing
Measured: 16 weeks
Secondary outcomes (5)
Number of angina attacks per week
Frequency of patient-reported daily diary of angina
Measured: 16 weeks
Short-acting nitrates intake per week
Frequency of patient-reported short-acting nitrates intake for symptom-relief
Measured: 16 weeks
Relative decrease in stress-induced myocardial ischemia during exercise echocardiogram
% of change in myocardial ischemia burden assessed during exercise echocardiogram stress test compared to baseline
Measured: 16 weeks
Relative change in the levels of oxidative stress biomarkers
% of change in the level of biomarkers of stress oxidative (nitrotyrosine, malondialdehyde and of reduced glutathione) compared to baseline
Measured: 16 weeks
Relative change in endothelium-dependent vasodilation during reactive hyperemia in the forearm
% of improvement in endothelium-dependent vasodilation assessed during reactive hyperemia (brachial artery) compared to baseline
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Apr 2020
- Study start3 Mar 2021 (estimated)
- Primary completion30 Sep 2021 (estimated)
- Study completion31 Dec 2021 (estimated)
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 Refractory 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients will randomly be assigned to receive either placebo or allopurinol 300mg once daily for four weeks, up titrate to 600mg for another 12 weeks for a total of 16 weeks of treatment.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ministry of Health, Brazil
- Sponsor type
- Other government
- Collaborators
- Fundação de Amparo à Pesquisa do Estado de São Paulo, InCor Heart Institute
- Responsible party
- Principal investigator, Luis Henrique W Gowdak, MD, PhD, InCor Heart Institute
- Investigators
- Luis Henrique W Gowdak, MD, PhD, Principal investigator, Heart Institute (InCor-HCFMUSP)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04368819
- Sponsor's protocol ID
- SDC 4781/18/132
- Other IDs
- 2018/22588-3, 2018
- Acronym
- ARAMIS
- Status last verified
- Feb 2021
- First submitted
- 23 Apr 2020
- Last updated
- 24 Feb 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: We must abide by the local regulations.
Publications
Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010 Jun 19;375(9732):2161-7. doi: 10.1016/S0140-6736(10)60391-1. Epub 2010 Jun 9.
PubMed 20542554
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single-center, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Allopurinol in Improving Ischemic Symptoms in Patients With Refractory Angina.
- ClinicalTrials.gov ID
- NCT04368819
- Acronym / sponsor ID
- ARAMIS / SDC 4781/18/132
- Conditions
- Refractory Angina
- Keywords
- angina, coronary artery disease, myocardial ischemia, treatment, allopurinol, cardiopulmonary exercising test, oxidative stress, stress echocardiogram
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Ministry of Health, BrazilOther government
- Collaborators
- Fundação de Amparo à Pesquisa do Estado de São Paulo, InCor Heart Institute
- Study start
- 3 Mar 2021 (estimated)
- Primary completion
- 30 Sep 2021 (estimated)
- Study completion
- 31 Dec 2021 (estimated)
- First posted
- 30 Apr 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.
Despite numerous advances in medical treatment and revascularization procedures for the treatment of patients with stable angina, debilitating symptoms that are unresponsive to conventional therapy may occur in patients unsuitable for revascularization, a condition known as refractory angina. Allopurinol, a methylxanthine oxidase inhibitor, is widely used in the treatment of gout and asymptomatic hyperuricemia. On the other hand, the anti-ischemic effects of allopurinol have been the subject of increasing interest. Therefore, the investigators will study the safety and efficacy of allopurinol in alleviating ischemic symptoms in patients with refractory angina already on optimal medical therapy.
Detailed description
One of the most common clinical presentations associated with coronary artery disease (CAD) is stable angina, which can be translated clinically into chest discomfort (or equivalent) evoked by different levels of physical activity depending on the extent of the disease. In the United States, it is estimated that 16.5 million individuals over 20 years of age have chronic ischemic heart disease, of which 3.4 million live with the diagnosis of angina pectoris. Refractory angina is a clinical condition characterized by the presence of debilitating symptoms secondary to CAD lasting more than three months in which the symptoms are attributed to objectively documented ischemia and not controlled with the combination of conventional antianginal agents and myocardial revascularization procedures. The estimated annual incidence of patients with refractory angina is between 50,000 and 200,000 new cases in the United States.
Allopurinol, a methylxanthine oxidase inhibitor, is widely used in the treatment of gout and asymptomatic hyperuricemia. The therapeutic potential of allopurinol in patients with cardiovascular disease has been the subject of increasing interest. In patients with CAD, the first study tested the role of allopurinol in improving exercise tolerance in 65 patients with stable angina documented by angiography and positive stress test for myocardial ischemia. After only six weeks of treatment, patients who received allopurinol showed a statistically significant increase in ergometry parameters, including time for ST-segment depression, total exercise time, and time until the onset of angina. There were no reports of adverse events. Considerable decrease in inflammatory markers and oxidative stress indicators has been demonstrated in patients with acute myocardial infarction receiving allopurinol versus placebo with a significant reduction in the risk of cardiovascular events in 2 years (10% vs. 30%, respectively). Therefore, the investigators will test the hypothesis that the use of allopurinol increases exercise tolerance and reduces angina attacks compared to placebo after 16 weeks of follow-up in patients with refractory angina.
Patients will be randomly selected to receive a placebo or allopurinol (600mg od) for 16 weeks. At baseline and after 16 weeks of treatment, exercise tolerance will be assessed through the cardiopulmonary exercising test, and myocardial ischemia will be determined using an exercise echocardiogram protocol. Biomarkers of oxidative stress will be measured in the blood and urine; endothelial-dependent vasodilation will be assessed using the reactive hyperemia protocol at the brachial artery.
For the sample size calculation, the investigators chose the primary outcome as "total exercise time (TTE) after intervention" based on the study by Noman et al. (Lancet 2010;375:2161-7). Thus, assuming that μ1 (allopurinol) = 396sec, μ2 (placebo) = 319sec and σ = 63sec, the investigators concluded that to be able to detect a difference between groups with 95% confidence (1-alfa) and 90% power (1-beta), 17 patients are needed in each study group. If the investigators consider a screen failure rate at 20%, a total of 40 patients will be needed, randomized 1:1.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Patients will randomly be assigned to receive either placebo or allopurinol 300mg once daily for four weeks, up titrate to 600mg for another 12 weeks for a total of 16 weeks of treatment.
| Arm | Type | Receives |
|---|---|---|
| Allopurinol | Active comparator | Drug: Allopurinol 300 MGAllopurinol 300mg P.O. once daily for four weeks followed by allopurinol 300mg P.O. twice daily for 12 weeks. |
| Placebo | Placebo comparator | Drug: Placebo oral tabletPlacebo pills indistinguishable from the active comparator given P.O. once daily for four weeks, followed by twice daily for 12 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Clinical diagnosis of stable angina in functional class (CCS) ≥ 2 for at least three months in patients taking maximally tolerated doses of at least three classes of antianginal agents
- Documentation of myocardial ischemia by any provocative functional test (exercise test, stress echocardiogram, myocardial perfusion scintigraphy or cardiac resonance)
- Signature of the Informed Consent Form
Key exclusion criteria (7 listed)
- Left ventricular dysfunction defined by LVEF < 30% on transthoracic echocardiogram
- Significant concomitant valve disease
- Chronic renal failure stage 4 or 5 (GFR < 30mL/min/1.73m2 calculated by the MDRD equation
- Significant liver dysfunction (Child-Pugh class C) or MELD value ≥ 15 calculated from creatinine, total bilirubin, and INR values
- Current use of warfarin
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 |
|---|---|---|
| Allopurinol 300 MGAlso: ZyloricAllopurinol 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks | Drug | Allopurinol |
| Placebo oral tabletAlso: PlaceboPlacebo 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks | Drug | Placebo |
Primary outcome
Increase in total exercise time (seconds) assessed by CPET
Time frame: 16 weeks
Total exercise duration during a maximal, symptom-limited cardiopulmonary exercise testing
5 secondary outcomes
Number of angina attacks per week
Time frame: 16 weeks
Short-acting nitrates intake per week
Time frame: 16 weeks
Relative decrease in stress-induced myocardial ischemia during exercise echocardiogram
Time frame: 16 weeks
Relative change in the levels of oxidative stress biomarkers
Time frame: 16 weeks
Relative change in endothelium-dependent vasodilation during reactive hyperemia in the forearm
Time frame: 16 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2021.
- Background: PubMed 20542554Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010 Jun 19;375(9732):2161-7. doi: 10.1016/S0140-6736(10)60391-1. Epub 2010 Jun 9.
- Individual participant dataSharing planned: No. We must abide by the local regulations.
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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.
Luis Henrique W Gowdak, MD, PhD principal investigator
Heart Institute (InCor-HCFMUSP)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Allopurinol 300 MG in people with Refractory Angina, run by Ministry of Health, Brazil at 1 site in Brazil.
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 3 inclusion and 7 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: status not confirmed, as of the sponsor's last update on 24 Feb 2021. 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 Brazil. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Luis Henrique W Gowdak, MD, PhD (+55-11-26615000 ext. 5929, luis.gowdak@incor.usp.br), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Increase in total exercise time (seconds) assessed by CPET (time frame: 16 weeks). 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 NCT04368819, 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 24 Feb 2021.