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Cardiometabolic Effects of Eplerenone in HIV Infection

Primary Purpose

Cardiac Steatosis, Hepatic Steatosis

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Inspra /Eplerenone

About this trial

This is an interventional treatment trial for Cardiac Steatosis focused on measuring Hepatic Steatosis, Cardiac Steatosis, Aldosterone, Eplerenone, Mineralcorticoid Receptor

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:
1. Increased waist circumference on the basis of National Cholesterol Education Program guidelines (> 102 cm in men and > 88 cm in women)
2. Hepatic steatosis established by hepatic MRI greater than or equal to 5% and/or liver biopsy within the last 12 months
3. HIV-infected, HIV viral load < 50 copies/mL and no change in ART regimen for at least 3 months
4. Age greater than or equal to 18 and less than or equal to 75 years
5. Agree to have samples stored for future research

EXCLUSION CRITERIA:

Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2, serum creatinine > 1.5 mg/dL
Serum potassium > 5.5 mEq/L, alanine aminotransferase > 2.5 times the upper limit of normal, hemoglobin (Hgb) < 11 g/dL
Uncontrolled hypertension: systolic blood pressure greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 100 mm Hg
A blood pressure < 90mmHg systolic or < 50mm Hg diastolic
Screening EKG with a significant heart block (e.g. PR > 300 ms) or an EKG determined significant by Cardiology consult.
Current hepatitis C infection, unless there has been a sustained virologic response for at least 12 months
Type 2 diabetes with microalbuminuria
Current or prior steroid use within past 6 months (except short-course or single-dose administration). Stable use of inhaled or nasal steroids are allowed.
Use of angiotensin converting enzyme (ACE) inhibitors, angiotensin reporter blockers (ARBs), potassium-sparing diuretics, and other medications that may increase the risk of hyperkalemia
Use of potassium supplementation or other medications known to increase potassium
Concomitant use of strong inhibitors and/or inducers ofof cytochrome P450 isozyme (CYP)3A4
If receiving testerone, estrogen or progesterone therapy, must be on a stable dose for at least 3 months.
Current use of growth hormone or growth hormone-releasing hormone
Current serious viral, bacterial, or other infection (excluding HIV)
Current active substance abuse/dependence
Substantial history of cardiovascular disease, including prior myocardial infarction (MI), congestive heart failure, or stroke
Contraindication to MRI
Pregnant or planning to become pregnant
Breastfeeding
Any condition that, in the opinion of the PI, may substantially increase the risk of participation

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

Intervention: Eplerenone will be administered for 6 months as follows: 25 mg once daily for 1 week and then 50 mg once daily for the remainder of the study.

Outcomes

Primary Outcome Measures

Improvement of Cardiac Steatosis: Mean Change in Intraventricular Septum Percentage of Lipid by MR Spectroscopy.

Mean change in intraventricular septum percentage of lipid by MR spectroscopy. This was calculated by subtracting the baseline intraventicular septum percentage value of lipid from the week 24 intraventicular septum percentage value of lipid by MR spectroscopy.

Improvement of Hepatic Steatosis: Mean Change in Hepatic Percentage of Lipid by MR Spectroscopy

Mean change in hepatic percentage of lipid by MR spectroscopy. This was calculated by subtracting the baseline hepatic percentage value of lipid from the week 24 hepatic percentage value of lipid by MR spectroscopy.

Secondary Outcome Measures

Full Information

NCT ID

NCT02629094

First Posted

December 10, 2015

Last Updated

June 21, 2018

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

1. Study Identification

Unique Protocol Identification Number

NCT02629094

Brief Title

Cardiometabolic Effects of Eplerenone in HIV Infection

Official Title

Cardiometabolic Effects of Eplerenone in HIV Infection

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Terminated

Study Start Date

December 2, 2015 (undefined)

Primary Completion Date

September 11, 2017 (Actual)

Study Completion Date

September 11, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Background: People with human immunodeficiency virus (HIV) are at a high risk of getting visceral or deep belly fat. Visceral fat can cause health problems like heart or liver disease. Researchers want to see if a blood pressure drug can help by blocking a hormone in the body. Objective: To see if eplerenone reduces fat stored in the heart muscle and liver in people with HIV and increased visceral fat. Eligibility: Adults ages 18 75 with HIV and increased waist circumference. Increased waist circumference is defined as more than 40 inches in men and more than 35 inches in women. Design: Participants will be screened with: Physical exam Medical history Blood tests Measurements of hips, waist, legs, arms, shoulders, and neck Magnetic resonance imaging (MRI) scan. They will lie on a table that slides into a machine. Electrocardiogram (EKG) to measure heart electrical activity Transient elastography, a special ultrasound to measure liver tissue stiffness A small piece their liver collected (optional) Participants will have a baseline visit: Physical exam Medical history Blood tests DEXA scan to measure body fat, muscle mass, and bone density. Participants will lie on a table while a very small dose of x-rays goes through the body. Resting energy expenditure (REE). This measures the amount of oxygen breathed in and carbon dioxide breathed out. Participants will get a 1-week supply of eplerenone. They will take one pill per day. Participants will have a follow-up visit 1 week later. They will have: Physical exam Medical history Blood tests 23-week supply of eplerenone Participants will have 5 more follow-up visits. Participants will have a final study visit, repeating many of the screening and baseline tests.

Detailed Description

HIV-infected individuals are at higher risk than uninfected people for developing cardiovascular disease. Visceral adipose tissue is also increased in HIV-infected people compared to uninfected individuals. Animal studies suggest that blockade of the mineralocorticoid receptor (MR) may have beneficial effects on cardiovascular and metabolic parameters via inhibition of adipocyte differentiation and triglyceride accumulation. We will examine the effects of the MR antagonist eplerenone (50 mg daily) on HIV-infected adults with abdominal fat accumulation in a 24-week, open-label, proof-of-concept study. Magnetic resonance imaging will be conducted at screening and the final study visit to evaluate cardiac and hepatic steatosis. We anticipate that blocking the effects of increased aldosterone secretion with eplerenone will significantly reduce intramyocardial lipid content and hepatic steatosis in this population. These effects may be accompanied by decreases in visceral adipose tissue, and improvements in dyslipidemia and inflammation, thereby improving cardiovascular health.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cardiac Steatosis, Hepatic Steatosis

Keywords

Hepatic Steatosis, Cardiac Steatosis, Aldosterone, Eplerenone, Mineralcorticoid Receptor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Intervention: Eplerenone will be administered for 6 months as follows: 25 mg once daily for 1 week and then 50 mg once daily for the remainder of the study.

Intervention Type

Drug

Intervention Name(s)

Inspra /Eplerenone

Intervention Description

Eplerenone is provided as 25- or 50-mg tablets that are to be taken orally. Subjects will be dosed at 25 mg daily for 1 week, and then 50 mg daily for 23 weeks. The total duration of dosing for each subject is 24 weeks.

Primary Outcome Measure Information:

Title

Improvement of Cardiac Steatosis: Mean Change in Intraventricular Septum Percentage of Lipid by MR Spectroscopy.

Description

Time Frame

24 weeks

Title

Improvement of Hepatic Steatosis: Mean Change in Hepatic Percentage of Lipid by MR Spectroscopy

Description

Time Frame

24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Increased waist circumference on the basis of National Cholesterol Education Program guidelines (> 102 cm in men and > 88 cm in women) Hepatic steatosis established by hepatic MRI greater than or equal to 5% and/or liver biopsy within the last 12 months HIV-infected, HIV viral load < 50 copies/mL and no change in ART regimen for at least 3 months Age greater than or equal to 18 and less than or equal to 75 years Agree to have samples stored for future research EXCLUSION CRITERIA: Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2, serum creatinine > 1.5 mg/dL Serum potassium > 5.5 mEq/L, alanine aminotransferase > 2.5 times the upper limit of normal, hemoglobin (Hgb) < 11 g/dL Uncontrolled hypertension: systolic blood pressure greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 100 mm Hg A blood pressure < 90mmHg systolic or < 50mm Hg diastolic Screening EKG with a significant heart block (e.g. PR > 300 ms) or an EKG determined significant by Cardiology consult. Current hepatitis C infection, unless there has been a sustained virologic response for at least 12 months Type 2 diabetes with microalbuminuria Current or prior steroid use within past 6 months (except short-course or single-dose administration). Stable use of inhaled or nasal steroids are allowed. Use of angiotensin converting enzyme (ACE) inhibitors, angiotensin reporter blockers (ARBs), potassium-sparing diuretics, and other medications that may increase the risk of hyperkalemia Use of potassium supplementation or other medications known to increase potassium Concomitant use of strong inhibitors and/or inducers ofof cytochrome P450 isozyme (CYP)3A4 If receiving testerone, estrogen or progesterone therapy, must be on a stable dose for at least 3 months. Current use of growth hormone or growth hormone-releasing hormone Current serious viral, bacterial, or other infection (excluding HIV) Current active substance abuse/dependence Substantial history of cardiovascular disease, including prior myocardial infarction (MI), congestive heart failure, or stroke Contraindication to MRI Pregnant or planning to become pregnant Breastfeeding Any condition that, in the opinion of the PI, may substantially increase the risk of participation

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Colleen M Hadigan, M.D.

Organizational Affiliation

National Institute of Allergy and Infectious Diseases (NIAID)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

17456578

Citation

Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12. doi: 10.1210/jc.2006-2190. Epub 2007 Apr 24.

Results Reference

background

PubMed Identifier

19505930

Citation

Hirata A, Maeda N, Hiuge A, Hibuse T, Fujita K, Okada T, Kihara S, Funahashi T, Shimomura I. Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice. Cardiovasc Res. 2009 Oct 1;84(1):164-72. doi: 10.1093/cvr/cvp191. Epub 2009 Jun 8.

Results Reference

background

PubMed Identifier

16424347

Citation

Suzuki J, Iwai M, Mogi M, Oshita A, Yoshii T, Higaki J, Horiuchi M. Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation. Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):917-21. doi: 10.1161/01.ATV.0000204635.75748.0f. Epub 2006 Jan 19.

Results Reference

background

PubMed Identifier

29509992

Citation

Chaudhury CS, Purdy JB, Liu CY, Morse CG, Stanley TL, Kleiner D, Hadigan C. Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease. Liver Int. 2018 May;38(5):797-802. doi: 10.1111/liv.13734. Epub 2018 Mar 31.

Results Reference

result

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Cardiometabolic Effects of Eplerenone in HIV Infection

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