HIV
Conditions
Keywords
Eplerenone, Cardiovascular Disease, Mineralocorticoid Receptor Antagonist, Coronary Vasculature, Myocardial Inflammation, Myocardial Fibrosis, Atherosclerosis, Aldosterone
Brief summary
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
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.
Interventions
DRUGEplerenone
Eplerenone 50mg by mouth twice daily
DRUGPlacebo
Placebo by mouth twice daily
BEHAVIORALLifestyle Modification
Counseling regarding diet and healthy activity
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Perfusion by PET | 12 Months | 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. |
| Myocardial Perfusion by MRI | 12 Months | Change (value at 12 months minus value at baseline) in myocardial perfusion assessed by myocardial blood flow measured via cardiac magnetic resonance imaging |
| Myocardial Inflammation | 12 Months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Markers of Systemic Inflammation hsCRP | 12 Months | Change (value at 12 months minus value at baseline) in plasma hsCRP |
| Markers of Immune Activation MCP-1 | 12 Months | Change (value at 12 months minus value at baseline) in plasma MCP-1 |
| Markers of Immune Activation sCD163 | 12 Months | Change (value at 12 months minus value at baseline) in plasma sCD163 |
| Markers of Subclinical Injury | 12 Months | Change (value at 12 months minus value at baseline) in serum NT-proBNP |
| Markers of Fibrosis | 12 Months | 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 |
| Coronary Plaque | 12 Months | 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 |
| Markers of Arterial Inflammation | 12 Months | Change (value at 12 months minus value at baseline) in plasma LpPLA2 |
| Assessment of Cardiac Structure by Left Ventricular Mass on Cardiac Imaging | 12 Months | Change (value at 12 months minus value at baseline) in left ventricular mass on cardiac magnetic resonance imaging |
| Assessment of Cardiac Systolic Function Via Cardiac Imaging | 12 Months | Change (value at 12 months minus value at baseline) in global circumferential strain (GCS) on cardiac magnetic resonance imaging |
| Assessment of Cardiac Diastolic Function Via Cardiac Imaging | 12 Months | Change (value at 12 months minus value at baseline) in left ventricular end diastolic volume on cardiac magnetic resonance imaging |
| Arterial Inflammation | 12 Months | 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 |
| Markers of Vascular Dysfunction | 12 Months | Change (value at 12 months minus value at baseline) in serum hs-cTnT |
| Markers of Systemic Inflammation hsIL-6 | 12 Months | Change (value at 12 months minus value at baseline) in plasma hsIL-6 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eplerenone Eplerenone 50 mg twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 12 months
Eplerenone: Eplerenone 50mg by mouth twice daily
Lifestyle Modification: Counseling regarding diet and healthy activity | 20 |
| Placebo Placebo twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 12 months
Placebo: Placebo by mouth twice daily
Lifestyle Modification: Counseling regarding diet and healthy activity | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | Eplerenone | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 7 | 55 years STANDARD_DEVIATION 7 | 56 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 33 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) White | 11 Participants | 22 Participants | 11 Participants |
| Region of Enrollment United States | 20 participants | 40 participants | 20 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 15 Participants | 30 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 0 / 20 |
| other Total, other adverse events | 12 / 20 | 11 / 20 |
| serious Total, serious adverse events | 1 / 20 | 0 / 20 |
Outcome results
Primary
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
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Myocardial Inflammation | 0.9 g/m^2 |
| Placebo | Myocardial Inflammation | -0.7 g/m^2 |
p-value: 0.38Kruskal-Wallis
Primary
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
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone | Myocardial Perfusion by MRI | 0.09 mL/min/g | Standard Deviation 0.56 |
| Placebo | Myocardial Perfusion by MRI | -0.53 mL/min/g | Standard Deviation 0.68 |
p-value: 0.03t-test, 2 sided
Primary
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.
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone | Myocardial Perfusion by PET | 0.01 unitless | Standard Deviation 0.64 |
| Placebo | Myocardial Perfusion by PET | -0.07 unitless | Standard Deviation 0.48 |
p-value: 0.72t-test, 2 sided
Secondary
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
Time frame: 12 Months
Population: Analyses performed on data available as part of a substudy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Arterial Inflammation | -12.4 percentage change |
| Placebo | Arterial Inflammation | 5.1 percentage change |
p-value: 0.003Kruskal-Wallis
Secondary
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
Time frame: 12 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone | Assessment of Cardiac Diastolic Function Via Cardiac Imaging | -13 mL | Standard Deviation 28 |
| Placebo | Assessment of Cardiac Diastolic Function Via Cardiac Imaging | 10 mL | Standard Deviation 26 |
p-value: 0.03t-test, 2 sided
Secondary
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
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Assessment of Cardiac Structure by Left Ventricular Mass on Cardiac Imaging | 1 g |
| Placebo | Assessment of Cardiac Structure by Left Ventricular Mass on Cardiac Imaging | 9 g |
p-value: 0.56Kruskal-Wallis
Secondary
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
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Assessment of Cardiac Systolic Function Via Cardiac Imaging | -1.3 percentage GCS |
| Placebo | Assessment of Cardiac Systolic Function Via Cardiac Imaging | 2.3 percentage GCS |
p-value: 0.03Kruskal-Wallis
Secondary
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
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Coronary Plaque | 0 score on a scale |
| Placebo | Coronary Plaque | 5 score on a scale |
p-value: 0.09Kruskal-Wallis
Secondary
Markers of Arterial Inflammation
Change (value at 12 months minus value at baseline) in plasma LpPLA2
Time frame: 12 Months
Population: Analyses performed on data available as part of a substudy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Arterial Inflammation | 3.0 ng/mL |
| Placebo | Markers of Arterial Inflammation | 2.6 ng/mL |
p-value: 0.73Kruskal-Wallis
Secondary
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
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Fibrosis | 25 ms |
| Placebo | Markers of Fibrosis | 1 ms |
p-value: 0.32Kruskal-Wallis
Secondary
Markers of Immune Activation MCP-1
Change (value at 12 months minus value at baseline) in plasma MCP-1
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Immune Activation MCP-1 | 285 pg/mL |
| Placebo | Markers of Immune Activation MCP-1 | 292 pg/mL |
p-value: 0.88t-test, 2 sided
Secondary
Markers of Immune Activation sCD163
Change (value at 12 months minus value at baseline) in plasma sCD163
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Immune Activation sCD163 | -275 ng/mL |
| Placebo | Markers of Immune Activation sCD163 | -160 ng/mL |
p-value: 0.17t-test, 2 sided
Secondary
Markers of Subclinical Injury
Change (value at 12 months minus value at baseline) in serum NT-proBNP
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Subclinical Injury | 19.4 ng/L |
| Placebo | Markers of Subclinical Injury | 2.8 ng/L |
p-value: 0.28t-test, 2 sided
Secondary
Markers of Systemic Inflammation hsCRP
Change (value at 12 months minus value at baseline) in plasma hsCRP
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Systemic Inflammation hsCRP | 189 ng/mL |
| Placebo | Markers of Systemic Inflammation hsCRP | 591 ng/mL |
p-value: 0.36t-test, 2 sided
Secondary
Markers of Systemic Inflammation hsIL-6
Change (value at 12 months minus value at baseline) in plasma hsIL-6
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Systemic Inflammation hsIL-6 | -0.8 pg/mL |
| Placebo | Markers of Systemic Inflammation hsIL-6 | 0.2 pg/mL |
p-value: 0.09t-test, 2 sided
Secondary
Markers of Vascular Dysfunction
Change (value at 12 months minus value at baseline) in serum hs-cTnT
Time frame: 12 Months
Population: Analyses performed on data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Markers of Vascular Dysfunction | 0.00 ng/L |
| Placebo | Markers of Vascular Dysfunction | 0.00 ng/L |
p-value: 0.03t-test, 2 sided