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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Eplerenone; Behavioral: Lifestyle Modification; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ages 40-65 years
2. Antiretroviral use (ART) >12 months and HIV viral load <100 copies/mL
3. VAT> 110cm2

Exclusion Criteria:

1. 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.
2. Unstable statin use <12 months. Stable use (>12 months) is allowed.
3. Use of full dose ritonavir, nelfinavir, clarithromycin, and other strong inhibitors of CYP3A4, as well as CYP3A4 inducers.
4. Continuous oral steroid use (equivalent to prednisone > 5 mg daily) within the last 3 months.
5. Uncontrolled diabetes requiring insulin and/or HbA1c > 7.5%.
6. Creatinine (Cr) > 1.5 mg/dL or estimated GFR<60 mL/min/1.73m2.
7. K > 5.5 mEq/L.
8. Hemoglobin < 10 g/dL.
9. Known liver disease or ALT >3x ULN.
10. History of congestive heart failure, stroke, myocardial infarction, or known coronary artery disease.
11. Pregnant, actively seeking pregnancy or breastfeeding.
12. Estrogen, progestin derivative, or other sex steroid use within last 3 months. Stable physiologic testosterone replacement (> 3 months) is acceptable.
13. Current bacterial or other infections.
14. Active substance abuse.
15. 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.
16. Previous reaction or contraindication to iodine-containing contrast media and gadolinium.
17. Coronary artery luminal narrowing >70% on coronary CTA.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

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

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Publications and helpful links

General Publications

• Srinivasa S, Fitch KV, Wong K, Torriani M, Mayhew C, Stanley T, Lo J, Adler GK, Grinspoon SK. RAAS Activation Is Associated With Visceral Adiposity and Insulin Resistance Among HIV-infected Patients. J Clin Endocrinol Metab. 2015 Aug;100(8):2873-82. doi: 10.1210/jc.2015-1461. Epub 2015 Jun 18.

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (Actual): March 17, 2022
• Study Completion (Actual): March 17, 2022

Study Registration Dates

• First Submitted: April 7, 2016
• First Submitted That Met QC Criteria: April 13, 2016
• First Posted (Estimated): April 15, 2016

Study Record Updates

• Last Update Posted (Actual): June 6, 2023
• Last Update Submitted That Met QC Criteria: June 2, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular Disease; Atherosclerosis; Myocardial Inflammation; Myocardial Fibrosis; Eplerenone; Mineralocorticoid Receptor Antagonist; Coronary Vasculature; Aldosterone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Eplerenone
• Other Study ID Numbers: 2016P000464

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No