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Allopurinol in Patients With Refractory Angina to Improve Ischemic Symptoms (ARAMIS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04368819
Recruitment Status : Enrolling by invitation
First Posted : April 30, 2020
Last Update Posted : May 7, 2020
Sponsor:
Collaborators:
Fundação de Amparo à Pesquisa do Estado de São Paulo
InCor Heart Institute
Information provided by (Responsible Party):
Luis Henrique W Gowdak, MD, PhD, InCor Heart Institute

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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.
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.
Estimated Study Start Date : May 1, 2020
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angina

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 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




Primary Outcome Measures :
  1. Increase in total exercise time (seconds) assessed by CPET [ Time Frame: 16 weeks ]
    Total exercise duration during a maximal, symptom-limited cardiopulmonary exercise testing


Secondary Outcome Measures :
  1. Number of angina attacks per week [ Time Frame: 16 weeks ]
    Frequency of patient-reported daily diary of angina

  2. Short-acting nitrates intake per week [ Time Frame: 16 weeks ]
    Frequency of patient-reported short-acting nitrates intake for symptom-relief

  3. 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

  4. 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

  5. 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


Other Outcome Measures:
  1. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

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


Locations
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Brazil
Heart Institute
Sao Paulo, SP, Brazil, 05403-000
Sponsors and Collaborators
Ministry of Health, Brazil
Fundação de Amparo à Pesquisa do Estado de São Paulo
InCor Heart Institute
Investigators
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Principal Investigator: Luis Henrique W Gowdak, MD, PhD Heart Institute (InCor-HCFMUSP)
Publications:
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Responsible Party: Luis Henrique W Gowdak, MD, PhD, Clinical Scientist, InCor Heart Institute
ClinicalTrials.gov Identifier: NCT04368819    
Other Study ID Numbers: SDC 4781/18/132
2018/22588-3 ( Other Grant/Funding Number: Fundação de Amparo à Pesquisa do Estado de São Paulo )
First Posted: April 30, 2020    Key Record Dates
Last Update Posted: May 7, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We must abide by the local regulations.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Luis Henrique W Gowdak, MD, PhD, InCor Heart Institute:
angina
coronary artery disease
myocardial ischemia
treatment
allopurinol
cardiopulmonary exercising test
oxidative stress
stress echocardiogram
Additional relevant MeSH terms:
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Angina Pectoris
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Chest Pain
Pain
Neurologic Manifestations
Allopurinol
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs