Allopurinol in Patients With Refractory Angina to Improve Ischemic Symptoms (ARAMIS)
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|ClinicalTrials.gov Identifier: NCT04368819|
Recruitment Status : Enrolling by invitation
First Posted : April 30, 2020
Last Update Posted : May 7, 2020
|Condition or disease||Intervention/treatment||Phase|
|Refractory Angina||Drug: Allopurinol 300 MG Drug: Placebo oral tablet||Phase 2 Phase 3|
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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|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.|
|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.|
|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.|
|Estimated Study Start Date :||May 1, 2020|
|Estimated Primary Completion Date :||July 31, 2021|
|Estimated Study Completion Date :||December 31, 2021|
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 Name: 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 Name: Placebo
- Increase in total exercise time (seconds) assessed by CPET [ Time Frame: 16 weeks ]Total exercise duration during a maximal, symptom-limited cardiopulmonary exercise testing
- Number of angina attacks per week [ Time Frame: 16 weeks ]Frequency of patient-reported daily diary of angina
- Short-acting nitrates intake per week [ Time Frame: 16 weeks ]Frequency of patient-reported short-acting nitrates intake for symptom-relief
- Relative decrease in stress-induced myocardial ischemia during exercise echocardiogram [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 16 weeks ]% of improvement in endothelium-dependent vasodilation assessed during reactive hyperemia (brachial artery) compared to baseline
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: 16 weeks ]All AE will be recorded during the 16 week period of the trial
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04368819
|Sao Paulo, SP, Brazil, 05403-000|
|Principal Investigator:||Luis Henrique W Gowdak, MD, PhD||Heart Institute (InCor-HCFMUSP)|