ARAMIS: Allopurinol in Patients With Refractory Angina to Improve Ischemic Symptoms

Sponsor

Ministry of Health, Brazil (Other)

Overall Status

Recruiting

CT.gov ID

NCT04368819

Collaborator

Fundação de Amparo à Pesquisa do Estado de São Paulo (Other), InCor Heart Institute (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief 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. 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.

Condition or Disease	Intervention/Treatment	Phase
Refractory Angina	Drug: Allopurinol 300 MG Drug: Placebo oral tablet	Phase 2/Phase 3

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

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

The placebo pills will be manufactured to be indistinguishable from the active treatment and dispensed by a registered pharmacist (who also will be blind to the intervention assigned to each individual participant) from our center.

Primary Purpose:

Treatment

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.

Anticipated Study Start Date :

Mar 3, 2021

Anticipated Primary Completion Date :

Sep 30, 2021

Anticipated Study Completion Date :

Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Allopurinol Allopurinol 300mg P.O. once daily for four weeks followed by allopurinol 300mg P.O. twice daily for 12 weeks.	Drug: Allopurinol 300 MG Allopurinol 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks Other Names: Zyloric
Placebo Comparator: Placebo Placebo pills indistinguishable from the active comparator given P.O. once daily for four weeks, followed by twice daily for 12 weeks.	Drug: Placebo oral tablet Placebo 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks Other Names: Placebo

Arm

Intervention/Treatment

Active Comparator: Allopurinol

Allopurinol 300mg P.O. once daily for four weeks followed by allopurinol 300mg P.O. twice daily for 12 weeks.

Drug: Allopurinol 300 MG

Allopurinol 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks

Other Names:

Zyloric

Placebo Comparator: Placebo

Placebo pills indistinguishable from the active comparator given P.O. once daily for four weeks, followed by twice daily for 12 weeks.

Drug: Placebo oral tablet

Placebo 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks

Other Names:

Placebo

Outcome Measures

Primary Outcome Measures

Increase in total exercise time (seconds) assessed by CPET [16 weeks]
Total exercise duration during a maximal, symptom-limited cardiopulmonary exercise testing

Secondary Outcome Measures

Number of angina attacks per week [16 weeks]
Frequency of patient-reported daily diary of angina
Short-acting nitrates intake per week [16 weeks]
Frequency of patient-reported short-acting nitrates intake for symptom-relief
Relative decrease in stress-induced myocardial ischemia during exercise echocardiogram [16 weeks]
% of change in myocardial ischemia burden assessed during exercise echocardiogram stress test compared to baseline
Relative change in the levels of oxidative stress biomarkers [16 weeks]
% of change in the level of biomarkers of stress oxidative (nitrotyrosine, malondialdehyde and of reduced glutathione) compared to baseline
Relative change in endothelium-dependent vasodilation during reactive hyperemia in the forearm [16 weeks]
% of improvement in endothelium-dependent vasodilation assessed during reactive hyperemia (brachial artery) compared to baseline

Other Outcome Measures

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [16 weeks]
All AE will be recorded during the 16 week period of the trial

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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