HIV, HIV Lipodystrophy
Conditions
Keywords
HIV, lipodystrophy, tesamorelin, Egrifta, growth hormone releasing hormone
Brief summary
HIV-infection and its treatment are often associated with an increase in belly fat, as well as abnormal cholesterol and problems metabolizing sugar. People with HIV infection and increased belly fat often have decreased growth hormone (GH) levels. Low GH levels may contribute independently to increased belly fat and to increased cardiovascular risk through effects on sugar metabolism, inflammation, and other mechanisms. Tesamorelin, a growth hormone releasing hormone (GHRH) analogue, has been shown to to reduce belly fat in patients with HIV-associated abdominal fat accumulation. However, the effects of tesamorelin on fat accumulation in the liver and muscle, sugar metabolism, and cardiovascular health are not yet known. The current study is designed to determine the effects of tesamorelin treatment on fat accumulation in the muscle and liver, insulin sensitivity and sugar metabolism, and markers of cardiovascular health including blood vessel thickness (carotid intima media thickness \[cIMT\]) and markers of inflammation in the body. The investigators hypothesize that tesamorelin will decrease fat accumulation in the liver and muscle and will decrease markers of inflammation, with either neutral or beneficial effects on glucose metabolism.
Interventions
DRUGtesamorelin
Tesamorelin (growth hormone releasing hormone) 2mg daily given by subcutaneous injection x 6 months during randomized phase, followed by 6 months of open-label tesamorelin at same dose
DRUGplacebo
Placebo 2mg daily given by subcutaneous injection for the first 6 months of the study, followed by an open-label phase of 6 months of tesamorelin (growth hormone releasing hormone) treatment, 2mg daily given by subcutaneous injection
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
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women age 18-65 2. Previously diagnosed HIV infection 3. Stable antiviral regimen for at least 12 weeks prior to enrollment 4. WC\>95 cm and WHR\>0.94 for male, WC\>94 cm and WHR\>0.88 for female occurring in the context of treatment for HIV disease 5. Subjective evidence of at least one of the following recent changes, occurring during the treatment of HIV disease: increased abdominal girth, relative loss of fat in the extremities, or relative loss of fat in the face 6. For female subjects 40yo or older, negative mammogram within one year of baseline
Exclusion criteria
1. Use of anti-diabetic agents, Megace, testosterone or any steroid use within 6 months of the study. Stable use of testosterone (\> 6 mos) at dose equivalent to 200 mg IM q 2 weeks or \< 10g/day to skin will be permitted. 2. Use of GH or GHRH within the past 6 months 3. Change in lipid lowering or antihypertensive regimen within 3 months of screening 4. Fasting blood sugar \> 126 mg/dL, SGOT \> 2.5 times ULN, HgB \< 12.0 g/dL, creatinine \> 1.4 mg/dL, CD4 count \< 200 5. Severe chronic illness or active malignancy or history of pituitary malignancy or history of colon cancer 6. For men, history of prostate cancer or evidence of prostate malignancy by PSA \> 5 ng/mL 7. Prior history of hypopituitarism, head irradiation or any other condition known to affect the GH axis 8. For women, positive urine hCG 9. Oral contraceptives, depo provera or combined progesterone-estrogen injections, transdermal contraceptive patches, estrogen or progestin coated IUD's within 6 months of the study. 10. Routine MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Liver Fat | 6 months | Hepatic fat as measured by magnetic resonance (MR) spectroscopy, and expressed by normalizing lipid to water and expressing as a percent (lipid-to-water percent). |
| Visceral Adipose Tissue | 6 months | Change in visceral adipose tissue area as measured by single-slice computed tomography (CT) scan at the L4 vertebra. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | 6 months | In a subgroup of 1/2 of the subjects, euglycemic hyperinsulinemic clamp will be performed to assess insulin-stimulated glucose uptake. Insulin stimulated glucose uptake (M) calculated using the method of DeFronzo is shown. |
| HbA1c | 6 months | Hemoglobin A1c. |
| Insulin Like Growth Factor 1 (IGF-I) | 6 months | Insulin Like Growth Factor 1 (IGF-I). |
| Lipid Panel | 6 months | Fasting lipids. Triglyceride value is given. |
| Intramyocellular Lipid | 6 months | Intramyocellular lipid (IMCL) as measured by magnetic resonance (MR) spectroscopy of the calf. Soleus IMCL normalized to creatinine (IMCL/Cr based on areas determined by spectroscopy) was measured. The change over 6 months is reported. |
| Glucose Tolerance | 6 months | Glucose tolerance as measured by standard oral glucose tolerance test. 2-hour glucose is given. |
| Adiponectin | 6 months | adiponectin. |
| Hemostatic Markers | 6 months | Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) measured in serum. |
| Carotid Intimal Medial Thickness (cIMT) | 6 months | Carotid Intimal Medial Thickness (cIMT). |
| Endogenous Growth Hormone Secretion | 6 months | Endogenous growth hormone (GH) concentrations measured by overnight frequent blood sampling every 20 minutes. Mean overnight GH concentration is given. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tesamorelin Tesamorelin (growth hormone releasing hormone) 2mg daily given subcutaneously x 6 months during randomized phase, followed by 6 months of open-label tesamorelin at same dose | 28 |
| Placebo (Inactive Injection) Placebo 2mg daily given subcutaneously for the first 6 months of the study, followed by 6 months of tesamorelin (growth hormone releasing hormone) 2mg daily during an open label phase | 22 |
| Total | 50 |
Baseline characteristics
| Characteristic | Tesamorelin | Placebo (Inactive Injection) | Total |
|---|---|---|---|
| Age, Continuous | 49 years | 53 years | 51.5 years |
| Race/Ethnicity, Customized Black | 6 participants | 3 participants | 9 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 20 participants | 14 participants | 34 participants |
| Region of Enrollment United States | 28 participants | 22 participants | 50 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 24 Participants | 18 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 28 | 21 / 22 |
| serious Total, serious adverse events | 3 / 28 | 3 / 22 |
Outcome results
Primary
Liver Fat
Hepatic fat as measured by magnetic resonance (MR) spectroscopy, and expressed by normalizing lipid to water and expressing as a percent (lipid-to-water percent).
Time frame: 6 months
Population: All available data were used; data were not available for some subjects. Data from 1 patient who was discontinued between the 3 and 6mo visits for adverse event are included. These data were obtained at a termination visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tesamorelin | Liver Fat | -2.0 Change in hepatic lipid-to-water % |
| Placebo (Inactive Injection) | Liver Fat | 0.9 Change in hepatic lipid-to-water % |
Primary
Visceral Adipose Tissue
Change in visceral adipose tissue area as measured by single-slice computed tomography (CT) scan at the L4 vertebra.
Time frame: 6 months
Population: Data from 1 patient who was discontinued between the 3 and 6mo visits for adverse event are included. These data were obtained at a termination visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tesamorelin | Visceral Adipose Tissue | -34 change in cm^2 after 6 months |
| Placebo (Inactive Injection) | Visceral Adipose Tissue | 8 change in cm^2 after 6 months |
Secondary
Adiponectin
adiponectin.
Time frame: 6 months
Population: All available data were used. Data were not available for 1 subject.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tesamorelin | Adiponectin | 0 Change in ng/mL |
| Placebo (Inactive Injection) | Adiponectin | 0 Change in ng/mL |
Secondary
Carotid Intimal Medial Thickness (cIMT)
Carotid Intimal Medial Thickness (cIMT).
Time frame: 6 months
Population: All available data were used.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tesamorelin | Carotid Intimal Medial Thickness (cIMT) | -0.03 Change in mm |
| Placebo (Inactive Injection) | Carotid Intimal Medial Thickness (cIMT) | -0.00 Change in mm |
Secondary
Endogenous Growth Hormone Secretion
Endogenous growth hormone (GH) concentrations measured by overnight frequent blood sampling every 20 minutes. Mean overnight GH concentration is given.
Time frame: 6 months
Population: All available data were used; data were not available for some subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tesamorelin | Endogenous Growth Hormone Secretion | 0.35 Change in ng/mL |
| Placebo (Inactive Injection) | Endogenous Growth Hormone Secretion | -0.01 Change in ng/mL |
Secondary
Glucose Tolerance
Glucose tolerance as measured by standard oral glucose tolerance test. 2-hour glucose is given.
Time frame: 6 months
Population: All available data were used; data were not available for some subjects.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tesamorelin | Glucose Tolerance | -1 Change in 2-hour glucose, mg/dL |
| Placebo (Inactive Injection) | Glucose Tolerance | -8 Change in 2-hour glucose, mg/dL |
Secondary
HbA1c
Hemoglobin A1c.
Time frame: 6 months
Population: All available data were used; data were not available for one subject.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tesamorelin | HbA1c | 0.20 Change in % |
| Placebo (Inactive Injection) | HbA1c | 0.02 Change in % |
Secondary
Hemostatic Markers
Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) measured in serum.
Time frame: 6 months
Population: Please note that we do not have data for these markers (neither PAI1 or tPA) because we did not have adequate funds to assess these.
Secondary
Insulin Like Growth Factor 1 (IGF-I)
Insulin Like Growth Factor 1 (IGF-I).
Time frame: 6 months
Population: All available data were used; data were not available for one subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tesamorelin | Insulin Like Growth Factor 1 (IGF-I) | 79 Change in ng/mL | Standard Deviation 92 |
| Placebo (Inactive Injection) | Insulin Like Growth Factor 1 (IGF-I) | 7 Change in ng/mL | Standard Deviation 62 |
Secondary
Insulin Sensitivity
In a subgroup of 1/2 of the subjects, euglycemic hyperinsulinemic clamp will be performed to assess insulin-stimulated glucose uptake. Insulin stimulated glucose uptake (M) calculated using the method of DeFronzo is shown.
Time frame: 6 months
Population: All available data were used; data were not available for some subjects.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tesamorelin | Insulin Sensitivity | 0.4 Change in mg/kg/min |
| Placebo (Inactive Injection) | Insulin Sensitivity | 0.7 Change in mg/kg/min |
Secondary
Intramyocellular Lipid
Intramyocellular lipid (IMCL) as measured by magnetic resonance (MR) spectroscopy of the calf. Soleus IMCL normalized to creatinine (IMCL/Cr based on areas determined by spectroscopy) was measured. The change over 6 months is reported.
Time frame: 6 months
Population: All available data were used; data were not available for some subjects. Data from 1 patient who was discontinued between the 3 and 6mo visits for adverse event are included. These data were obtained at a termination visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tesamorelin | Intramyocellular Lipid | -1.7 Change in ratio of IMCL/Cr |
| Placebo (Inactive Injection) | Intramyocellular Lipid | -0.2 Change in ratio of IMCL/Cr |
Secondary
Lipid Panel
Fasting lipids. Triglyceride value is given.
Time frame: 6 months
Population: All available data were used; data were not available for one subject.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tesamorelin | Lipid Panel | -25 Change in triglyceride, mg/dL |
| Placebo (Inactive Injection) | Lipid Panel | -10 Change in triglyceride, mg/dL |