HIV
Conditions
Keywords
HIV-infection, eplerenone, aldosterone, visceral fat, lipodystrophy
Brief summary
The purpose of this study is to test the effects of a drug, eplerenone, along with lifestyle modification to affect sugar metabolism, body fat distribution, and cardiovascular health in HIV-infected individuals. In non-HIV-infected individuals, recent data has shown that aldosterone, a hormone that regulates salt and water balance, is increased in association with increased belly fat and decreased insulin sensitivity. In HIV-infected individuals, aldosterone appears to be higher in individuals with increased belly fat, and increased aldosterone appears to be strongly associated with impaired sugar metabolism. In this study, the investigators will test the effects of eplerenone, which is a medication that blocks the actions of aldosterone, along with lifestyle modification. The investigators hypothesize that eplerenone may improve sugar metabolism, improve markers of cardiovascular health, and reduce fat accumulation in liver and muscle.
Detailed description
The study is 12 months long, with two phases. In the initial, 6-month phase, volunteers are randomly assigned to receive either eplerenone or placebo (an inactive pill). In addition, all volunteers will receive counseling about healthy diet and lifestyle, and will be asked to follow guidelines for a healthy level of physical activity. In the second 6-months of the study, all volunteers will continue to receive lifestyle modification and all will receive eplerenone.
Interventions
DRUGEplerenone and lifestyle
eplerenone 50mg by mouth daily as well as lifestyle counseling
OTHERplacebo and lifestyle
placebo pill daily and lifestyle counseling
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
30 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Increased waist circumference based on NCEP guidelines (\>102cm in men and \>88cm in women) and impaired glucose tolerance (either IFG \> 100 mg/dL but \< 126 mg/dL or 2hr glucose \> 140 mg/dl but \< 200 mg/dL, or fasting insulin \>12 uIU/mL) 2. HIV positive for 5y and on a stable ART regimen for at least 12 months 3. Age ≥ 30 and ≤ 65 years of age
Exclusion criteria
1. ACE Inhibitor, ARB, verapamil, or spironolactone 2. Potassium supplementation 3. Estimated GFR\<60, creatinine \> 1.5 mg/dL 4. Serum K \> 5.5 mEq/L, ALT \> 2.5 times the upper limit of normal, Hgb \< 11g/dL 5. Uncontrolled hypertension (SBP ≥ 160 or DBP ≥ 100) 6. Current or prior steroid use within past 6 months 7. Known history of diabetes mellitus or current use of anti-diabetic medications 8. Concomitant use of full dose ritonavir, nelfinavir, clarithromycin and other strong inhibitors of CYP34A 9. Use of St. John's Wart (CYP3A4 inducer) 10. Pregnant or actively seeking pregnancy, breastfeeding 11. For women: Pregnant or actively seeking pregnancy, breastfeeding, failure to use an acceptable non-hormonal form of birth control, including abstinence, barrier contraceptives, or non-hormonal IUD. 12. Estrogen or progestational derivative use within 3 months 13. Testosterone use for non-physiologic purposes, or physiologic testosterone replacement for \< 3 months. 14. Current growth hormone or growth hormone releasing hormone use 15. Current viral, bacterial or other infections (excluding HIV) 16. Current active substance abuse 17. Patients with a significant history of cardiovascular disease, including prior MI or stroke
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Insulin Stimulated Glucose Uptake | 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Liver Fat | 6 months | — |
| Intramyocellular Lipid | 6 months | — |
| Flow Mediated Vasodilation | 6 months | — |
| Potassium | 6 months | — |
| Hemoglobin A1c | 6 months | — |
| Visceral Adipose Tissue | 6 months | — |
| Plasminogen Activator Inhibitor 1 | 6 months | — |
| Adiponectin | 6 months | — |
| Markers of Systemic Inflammation | 6 months | IL-6 |
| Markers of Immune Activation | 6 months | MCP-1 |
| C-Reactive Protein | 6 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eplerenone and Lifestyle First 6 months: eplerenone 50mg daily along with lifestyle modification (counseling regarding lifestyle and diet, as well as following healthy activity guidelines) Second 6 months: same (eplerenone open label during second 6 months)
Eplerenone and lifestyle: eplerenone 50mg by mouth daily as well as lifestyle counseling | 25 |
| Placebo and Lifestyle First 6 months: placebo pill daily along with lifestyle modification (counseling regarding lifestyle and diet, as well as following healthy activity guidelines) Second 6 months: eplerenone (open label) 50mg daily along with continued lifestyle modification
placebo and lifestyle: placebo pill daily and lifestyle counseling | 21 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo and Lifestyle | Eplerenone and Lifestyle |
|---|---|---|---|
| Adiponectin | 4527 pg/mL | 4673 pg/mL | 4016 pg/mL |
| Age, Continuous | 51 years STANDARD_DEVIATION 6 | 52 years STANDARD_DEVIATION 6 | 49 years STANDARD_DEVIATION 6 |
| C-reactive Protein | 3.4 mg/L | 3.7 mg/L | 3.3 mg/L |
| Flow Mediated Vasodilation | 13.0 percentage of maximum change | 13.4 percentage of maximum change | 13.0 percentage of maximum change |
| Hemoglobin A1c | 5.7 percentage | 5.8 percentage | 5.7 percentage |
| Insulin Stimulated Glucose Uptake | 7.44 mg/min per μIU/ml | 7.52 mg/min per μIU/ml | 7.26 mg/min per μIU/ml |
| Intramyocellular Lipid | 0.4 percentage of intramyocellular lipid | 0.3 percentage of intramyocellular lipid | 0.5 percentage of intramyocellular lipid |
| Liver Fat | 5 percentage of intrahepatic lipid | 5 percentage of intrahepatic lipid | 5 percentage of intrahepatic lipid |
| Markers of Immune Activation | 198 pg/mL STANDARD_DEVIATION 66 | 191 pg/mL STANDARD_DEVIATION 51 | 205 pg/mL STANDARD_DEVIATION 78 |
| Markers of Systemic Inflammation | 9.1 pg/mL | 7.9 pg/mL | 10.2 pg/mL |
| Plasminogen Activator Inhibitor 1 | 36.9 ng/mL STANDARD_DEVIATION 18.3 | 37.0 ng/mL STANDARD_DEVIATION 18.7 | 36.7 ng/mL STANDARD_DEVIATION 18.3 |
| Potassium | 4.1 mEq/L STANDARD_DEVIATION 0.2 | 4.0 mEq/L STANDARD_DEVIATION 0.2 | 4.1 mEq/L STANDARD_DEVIATION 0.2 |
| 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 | 20 Participants | 11 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 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 | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 9 Participants | 15 Participants |
| Region of Enrollment United States | 46 Participants | 21 Participants | 25 Participants |
| Sex: Female, Male Female | 16 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 30 Participants | 15 Participants | 15 Participants |
| Visceral Adipose Tissue | 230 cm^2 | 241 cm^2 | 215 cm^2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 21 |
| other Total, other adverse events | 13 / 25 | 11 / 21 |
| serious Total, serious adverse events | 0 / 25 | 0 / 21 |
Outcome results
Primary
Insulin Stimulated Glucose Uptake
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Insulin Stimulated Glucose Uptake | 7.70 mg/min per μIU/ml |
| Placebo and Lifestyle | Insulin Stimulated Glucose Uptake | 8.58 mg/min per μIU/ml |
Comparison: Change in Insulin Stimulated Glucose Uptake measured during euglycemic hyperinsulinemic clamp procedure from baseline to 6 monthsp-value: 0.71Wilcoxon (Mann-Whitney)
Secondary
Adiponectin
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Adiponectin | 4015 pg/mL |
| Placebo and Lifestyle | Adiponectin | 4014 pg/mL |
Comparison: Change in Adiponectin from baseline to 6 monthsp-value: 0.78Wilcoxon (Mann-Whitney)
Secondary
C-Reactive Protein
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | C-Reactive Protein | 2.8 mg/L |
| Placebo and Lifestyle | C-Reactive Protein | 2.8 mg/L |
Comparison: Change in C-Reactive Protein from baseline to 6 monthsp-value: 0.1Wilcoxon (Mann-Whitney)
Secondary
Flow Mediated Vasodilation
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Flow Mediated Vasodilation | 15.3 percentage of maximum change |
| Placebo and Lifestyle | Flow Mediated Vasodilation | 9.6 percentage of maximum change |
Comparison: Change in Flow Mediated Vasodilation (maximum percentage) from baseline to 6 monthsp-value: 0.44Wilcoxon (Mann-Whitney)
Secondary
Hemoglobin A1c
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Hemoglobin A1c | 5.7 percentage |
| Placebo and Lifestyle | Hemoglobin A1c | 5.8 percentage |
Comparison: Change in Hemoglobin A1c from baseline to 6 monthsp-value: 0.7Wilcoxon (Mann-Whitney)
Secondary
Intramyocellular Lipid
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Intramyocellular Lipid | 0.4 percentage of intramyocellular lipid |
| Placebo and Lifestyle | Intramyocellular Lipid | 0.4 percentage of intramyocellular lipid |
Comparison: Change in Intramyocellular Lipid of calf muscles as measured by magnetic resonance spectroscopy from baseline to 6 monthsp-value: 0.04Wilcoxon (Mann-Whitney)
Secondary
Liver Fat
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Liver Fat | 6 percentage of intrahepatic lipid |
| Placebo and Lifestyle | Liver Fat | 4 percentage of intrahepatic lipid |
Comparison: Change in Liver Fat (Intrahepatic Lipid) as measured by magnetic resonance spectroscopy from baseline to 6 monthsp-value: 0.51Wilcoxon (Mann-Whitney)
Secondary
Markers of Immune Activation
MCP-1
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone and Lifestyle | Markers of Immune Activation | 205 pg/mL | Standard Error 19 |
| Placebo and Lifestyle | Markers of Immune Activation | 210 pg/mL | Standard Error 17 |
Comparison: Change in MCP-1 from baseline to 6 monthsp-value: 0.04t-test, 2 sided
Secondary
Markers of Systemic Inflammation
IL-6
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Markers of Systemic Inflammation | 9.8 pg/mL |
| Placebo and Lifestyle | Markers of Systemic Inflammation | 8.9 pg/mL |
Comparison: Change in IL-6 from baseline to 6 monthsp-value: 0.1Wilcoxon (Mann-Whitney)
Secondary
Plasminogen Activator Inhibitor 1
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone and Lifestyle | Plasminogen Activator Inhibitor 1 | 35 ng/mL | Standard Error 3 |
| Placebo and Lifestyle | Plasminogen Activator Inhibitor 1 | 35 ng/mL | Standard Error 3 |
Comparison: Change in Plasminogen Activator Inhibitor 1 from baseline to 6 monthsp-value: 0.37t-test, 2 sided
Secondary
Potassium
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone and Lifestyle | Potassium | 4.2 mEq/L | Standard Error 0.1 |
| Placebo and Lifestyle | Potassium | 4.2 mEq/L | Standard Error 0 |
Comparison: Mean serum measurements of Potassiump-value: 0.07t-test, 2 sided
Secondary
Visceral Adipose Tissue
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone and Lifestyle | Visceral Adipose Tissue | 231 cm^2 |
| Placebo and Lifestyle | Visceral Adipose Tissue | 233 cm^2 |
Comparison: Change in Visceral Adipose Tissue area as measured by magnetic resonance imaging of the abdomen from baseline to 6 monthsp-value: 0.42Wilcoxon (Mann-Whitney)