Effects of Eplerenone on Cardiovascular Disease in HIV (MIRACLE HIV Study)

Study Overview
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Brief Summary
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HIV-infected individuals treated with antiretroviral medications are living longer, but have an increased risk of heart disease when compared to non-HIV-infected individuals. A hormone called aldosterone, which regulates blood pressure and sodium balance, is elevated in the HIV population in association with with increased belly fat and altered glucose metabolism. Elevations in aldosterone hormone may also be associated with abnormal blood flow, inflammation, and coronary plaque in the heart. This study is being conducted to evaluate whether therapies to reduce the actions of aldosterone may decrease the burden and progression of heart disease in the HIV population.

Detailed Description
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This is a 12 month randomized, placebo controlled study enrolling HIV-infected individuals with no known history of cardiovascular disease. Eplerenone is a mineralocorticoid receptor antagonist, which can block aldosterone activation. This medication is approved by the FDA for high blood pressure and heart failure. This study aims to investigate the effect of eplerenone on other measures of cardiovascular disease in HIV. Using PET, MRI, and CT imaging technology, this study will evaluate whether eplerenone can improve coronary flow reserve and myocardial inflammation/fibrosis, in addition to atherosclerotic plaque build-up among the HIV population. The study also includes teaching on lifestyle modification to promote a healthy diet and exercise program.There are 3 overnight visits in addition to safety visits.

Official Title
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Mineralocorticoid Receptor Antagonism for Cardiovascular Health in HIV--The MIRACLE HIV Study

Conditions
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HIV

Intervention / Treatment
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* Drug: Eplerenone
* Drug: Placebo
* Behavioral: Lifestyle Modification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 40-65 years Antiretroviral use (ART) >12 months and HIV viral load <100 copies/mL VAT> 110cm2 Exclusion Criteria: Antihypertensive use including, ACE Inhibitor, ARB, MR blockade, diuretic, potassium (K) supplementation; or BP>140/90 mmHg. Stable use (>3 months) of beta-blockers or calcium channel blockers (CCB) (except verapamil) is allowed. Unstable statin use <12 months. Stable use (>12 months) is allowed. Use of full dose ritonavir, nelfinavir, clarithromycin, and other strong inhibitors of CYP3A4, as well as CYP3A4 inducers. Continuous oral steroid use (equivalent to prednisone > 5 mg daily) within the last 3 months. Uncontrolled diabetes requiring insulin and/or HbA1c > 7.5%. Creatinine (Cr) > 1.5 mg/dL or estimated GFR<60 mL/min/1.73m2. K > 5.5 mEq/L. Hemoglobin < 10 g/dL. Known liver disease or ALT >3x ULN. History of congestive heart failure, stroke, myocardial infarction, or known coronary artery disease. Pregnant, actively seeking pregnancy or breastfeeding. Estrogen, progestin derivative, or other sex steroid use within last 3 months. Stable physiologic testosterone replacement (> 3 months) is acceptable. Current bacterial or other infections. Active substance abuse. Significant radiation exposure over the course of the year prior to randomization (e.g., radiation therapy, PCI, catheter ablation of arrhythmia) within 12 months of randomization. Previous reaction or contraindication to iodine-containing contrast media and gadolinium. Coronary artery luminal narrowing >70% on coronary CTA.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eplerenone<br>Eplerenone 50 mg twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 12 months | Drug: Eplerenone<br>* Eplerenone 50mg by mouth twice daily<br>Behavioral: Lifestyle Modification<br>* Counseling regarding diet and healthy activity<br>|
| Placebo Comparator: Placebo<br>Placebo twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 12 months | Drug: Placebo<br>* Placebo by mouth twice daily<br>Behavioral: Lifestyle Modification<br>* Counseling regarding diet and healthy activity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Perfusion by PET | Change (value at 12 months minus value at baseline) in myocardial perfusion assessed by coronary flow reserve measured via cardiac positron emission tomography. Coronary flow reserve is given by the ratio of blood flow at stress during maximal dilation of the coronary arteries to blood flow at rest. | 12 Months | 
| Myocardial Perfusion by MRI | Change (value at 12 months minus value at baseline) in myocardial perfusion assessed by myocardial blood flow measured via cardiac magnetic resonance imaging | 12 Months | 
| Myocardial Inflammation | Change (value at 12 months minus value at baseline) in myocardial inflammation measured by extracellular mass index (a measure of the inflammation within the heart) via cardiac magnetic resonance imaging | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary Plaque | Change (value at 12 months minus value at baseline) in coronary plaque measured via coronary computed tomography angiogram assessed by coronary calcium score Scale: minimum 0 to maximum no limit, higher score indicates more plaque | 12 Months | 
| Markers of Vascular Dysfunction | Change (value at 12 months minus value at baseline) in serum hs-cTnT | 12 Months | 
| Markers of Systemic Inflammation hsIL-6 | Change (value at 12 months minus value at baseline) in plasma hsIL-6 | 12 Months | 
| Markers of Systemic Inflammation hsCRP | Change (value at 12 months minus value at baseline) in plasma hsCRP | 12 Months | 
| Markers of Immune Activation MCP-1 | Change (value at 12 months minus value at baseline) in plasma MCP-1 | 12 Months | 
| Markers of Immune Activation sCD163 | Change (value at 12 months minus value at baseline) in plasma sCD163 | 12 Months | 
| Markers of Subclinical Injury | Change (value at 12 months minus value at baseline) in serum NT-proBNP | 12 Months | 
| Markers of Fibrosis | Change (value at 12 months minus value at baseline) in myocardial fibrosis measured by T1 (a signal intensity that measures fibrosis) via cardiac magnetic resonance imaging | 12 Months | 
| Arterial Inflammation | Percentage change (value at 12 months minus value at baseline) in target to background ratio (a measure of arterial inflammation) of the index vessel measured via positron emission tomography/computed tomography | 12 Months | 
| Markers of Arterial Inflammation | Change (value at 12 months minus value at baseline) in plasma LpPLA2 | 12 Months | 
| Assessment of Cardiac Structure by Left Ventricular Mass on Cardiac Imaging | Change (value at 12 months minus value at baseline) in left ventricular mass on cardiac magnetic resonance imaging | 12 Months | 
| Assessment of Cardiac Systolic Function Via Cardiac Imaging | Change (value at 12 months minus value at baseline) in global circumferential strain (GCS) on cardiac magnetic resonance imaging | 12 Months | 
| Assessment of Cardiac Diastolic Function Via Cardiac Imaging | Change (value at 12 months minus value at baseline) in left ventricular end diastolic volume on cardiac magnetic resonance imaging | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eplerenone, Cardiovascular Disease, Mineralocorticoid Receptor Antagonist, Coronary Vasculature, Myocardial Inflammation, Myocardial Fibrosis, Atherosclerosis, Aldosterone