Tesamorelin Effects on Liver Fat and Histology in HIV
Study Details
Study Description
Brief Summary
Liver disease is one of the leading co-morbidities of human immunodeficiency virus (HIV) infection, and nonalcoholic fatty liver disease (NAFLD) is present in approximately 30-40% of patients with HIV infection. Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD in which increased liver fat is also accompanied by inflammation, cellular damage, and fibrosis.
NAFLD is most prevalent in patients who also have increased visceral adiposity, and our group has previously shown that HIV-infected individuals with increased visceral adiposity generally have decreased growth hormone secretion. Tesamorelin is a growth hormone releasing hormone (GHRH) analogue that increases endogenous growth hormone secretion. Tesamorelin is FDA-approved for the reduction of visceral fat in HIV-infected individuals. In a previous study, treatment with tesamorelin in HIV-infected individuals selected for abdominal adiposity reduced liver fat. The current study is designed to test the effect of tesamorelin on liver fat and steatohepatitis in HIV-infected individuals who have NAFLD. The investigators hypothesize that tesamorelin will reduce liver fat and will also ameliorate the inflammation, fibrosis, and hepatocellular damage seen in conjunction with NASH.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Tesamorelin tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. |
Drug: tesamorelin
Other Names:
|
| Placebo Comparator: Placebo placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. |
Drug: Placebo
inactive substance that looks like tesamorelin
|
Outcome Measures
Primary Outcome Measures
- Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy [change between baseline and 12 months]
change (value at 12 months minus value at baseline). Hepatic fat fraction is a standardized measure used to describe the percent fat in the liver. As it is determined by spectroscopy, it is quantified by the area under the lipid peak, standardized to the total area under the (lipid peak + water peak). Using 1-H Magnetic resonance spectroscopy to quantify liver fat in this manner was first described by Longo R et al., Invest Radiol, 1993, 28(4):297-302.
Secondary Outcome Measures
- Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score [change between baseline and 12 months]
change (value at 12 months minus value at baseline). The nonalcoholic fatty liver disease (NAFLD) activity score is a standardized histological quantification of NAFLD severity designed and validated by the Nonalcoholic Steatohepatitis Clinical Research Network (Kleiner DE et al., Hepatology, 2005, 41(6):1313-1321). The score is the sum of three semi-quantitative histological grades: steatosis, graded from 0 [<5% liver fat] to grade 3 [>66% liver fat] lobular inflammation, graded from 0 [no foci of inflammation] to 3 [>4 foci per 200x field] hepatocellular ballooning, graded from 0 [no ballooning] to 2 [many cells/prominent ballooning] The "total" NAFLD activity score, a sum of the three components below, ranges from 0 to 8, with a higher score generally representing greater severity of NAFLD/nonalcoholic steatohepatitis.
- Change in Alanine Aminotransferase (ALT) [change from baseline to 12 months]
change (value at 12 months minus value at baseline)
- Change in Aspartate Aminotransferase (AST) [change from baseline to 12 months]
change (value at 12 months minus value at baseline)
Eligibility Criteria
Criteria
Inclusion criteria:
-
Men and women 18-70yo
-
HIV-infection and treatment with a stable antiretroviral regimen for ≥ 6 months
-
Hepatic steatosis as demonstrated by liver fat fraction ≥5% on 1H-MRS
-
Hepatitis C antibody negative, or, if Hepatitis C antibody positive, either: a) known clinical disease, successful therapy ≥1 year prior to baseline and undetectable HCV RNA, or b) HCV resolved spontaneously and undetectable HCV RNA. Hepatitis B surface antigen negative at screen visit
-
For females ≥50yo, negative mammogram within 1 year of baseline visit
-
If use of Vitamin E ≥400 IU daily (in any formulation), stable dose for ≥6 months prior to study.
Exclusion criteria:
-
Heavy alcohol use defined as consumption of more than 20g daily for women or more than 30g daily for men for at least 3 consecutive months over the past 5 years
-
Use of insulin or thiazoledinediones (TZDs), or HbA1c ≥7%. Individuals with mild diabetes that is well-controlled with diet and/or oral anti-diabetic agents besides TZDs will be included. Use of oral anti-diabetics must have been stable for ≥6 months prior to study entry.
-
Known diabetic retinopathy.
-
Known cirrhosis, or Child-Pugh score ≥7, stage 4 fibrosis on biopsy, or clinical evidence of cirrhosis or portal hypertension on imaging or exam.
-
Chronic corticosteroid use except intermittent use of topical steroid creams and/or prior short-term physiologic corticosteroid use in the ≤ 6 months prior to baseline visit
-
Chronic use of methotrexate, amiodarone, or tamoxifen
-
Known diagnosis of Alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis
-
Use of GH or GHRH within the past 1 year
-
Change in lipid lowering or anti-hypertensive regimen within 3 months of screening
-
HgB < 11.0 g/dL, CD4 < 100 th/mm3, or HIV viral load > 400 copies/mL
-
Active malignancy
-
For men, history of prostate cancer or evidence of prostate malignancy by PSA > 5 ng/mL
-
Severe chronic illness judged by the investigator to present a contraindication to participation
-
History of hypopituitarism, head irradiation or any other condition known to affect the GH axis
-
Use of physiologic testosterone (men) or estrogen or progesterone (women) unless stable use for a year or more prior to study entry
-
Routine MRI exclusion criteria such as the presence of a pacemaker or cerebral aneurysm clip
-
Previous weight loss surgery
-
For women, positive pregnancy test performed in a CLIA certified laboratory using a test with a sensitivity of at least 25mIU/mL, or breastfeeding.
-
Known hypersensitivity to tesamorelin or mannitol
-
Unwillingness to abstain from the conception process during the study (i.e., must agree not to participate in an active attempt to become pregnant or impregnate, donate sperm, or participate in in vitro fertilization)
-
Unwillingness to use one (for males) or two (for females) reliable methods of contraception while engaging in heterosexual intercourse during the study. Acceptable methods for women include hormonal contraception (estrogen/progesterone or progesterone-only formulations) if stable for a year or more prior to study entry, intrauterine device, or barrier methods (condom, or diaphragm with spermicide). Acceptable methods for males include condom use. This requirement does not apply to women who have been post-menopausal for at least 24 consecutive months or have undergone surgical sterilization, or to men who have undergone surgical sterilization or have documented azoospermia.
-
Not willing or able to adhere to dose schedules and required procedures per protocol
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health | Bethesda | Maryland | United States | 20892 |
| 2 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
Sponsors and Collaborators
- Massachusetts General Hospital
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Steven K Grinspoon, MD, MGH
Study Documents (Full-Text)
More Information
Publications
None provided.- 1U01AI115711
- U01AI115711
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 1 subject was randomized to tesamorelin but self-discontinued during the baseline visit, prior to receiving any study drug. This individual is included in baseline characteristics but is not counted as starting tesamorelin (hence the discrepancy between 61 total enrolled and the 30 in tesamorelin and 30 in placebo group shown in participant flow). |
| Arm/Group Title | Tesamorelin | Placebo |
|---|---|---|
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin |
| Period Title: Overall Study | ||
| STARTED | 30 | 30 |
| Received Follow-up Imaging | 26 | 28 |
| COMPLETED | 21 | 26 |
| NOT COMPLETED | 9 | 4 |
Baseline Characteristics
| Arm/Group Title | Tesamorelin | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin | Total of all reporting groups |
| Overall Participants | 31 | 30 | 61 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
52
(8)
|
54
(7)
|
53
(7)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
24
77.4%
|
24
80%
|
48
78.7%
|
| Male |
7
22.6%
|
6
20%
|
13
21.3%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| White (all ethnicities) |
21
67.7%
|
19
63.3%
|
40
65.6%
|
| Black (all ethnicities) |
8
25.8%
|
10
33.3%
|
18
29.5%
|
| Other (all ethnicities) |
2
6.5%
|
1
3.3%
|
3
4.9%
|
| Hepatic Fibrosis Stage (Count of Participants) | |||
| Stage 0 (No Fibrosis) |
15
48.4%
|
18
60%
|
33
54.1%
|
| Stage 1 Fibrosis |
4
12.9%
|
5
16.7%
|
9
14.8%
|
| Stage 2 Fibrosis |
6
19.4%
|
4
13.3%
|
10
16.4%
|
| Stage 3 Fibrosis |
4
12.9%
|
2
6.7%
|
6
9.8%
|
| Data Not Available |
2
6.5%
|
1
3.3%
|
3
4.9%
|
Outcome Measures
| Title | Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy |
|---|---|
| Description | change (value at 12 months minus value at baseline). Hepatic fat fraction is a standardized measure used to describe the percent fat in the liver. As it is determined by spectroscopy, it is quantified by the area under the lipid peak, standardized to the total area under the (lipid peak + water peak). Using 1-H Magnetic resonance spectroscopy to quantify liver fat in this manner was first described by Longo R et al., Invest Radiol, 1993, 28(4):297-302. |
| Time Frame | change between baseline and 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| These are participants who had magnetic resonance spectroscopy for hepatic fat fraction at 0 and 12 months. This is different from the primary analysis population reported in the manuscript. |
| Arm/Group Title | Tesamorelin | Placebo |
|---|---|---|
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin |
| Measure Participants | 20 | 25 |
| Mean (Standard Deviation) [percent (hepatic fat fraction)] |
-4.7
(6.6)
|
0.0
(4.1)
|
| Title | Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score |
|---|---|
| Description | change (value at 12 months minus value at baseline). The nonalcoholic fatty liver disease (NAFLD) activity score is a standardized histological quantification of NAFLD severity designed and validated by the Nonalcoholic Steatohepatitis Clinical Research Network (Kleiner DE et al., Hepatology, 2005, 41(6):1313-1321). The score is the sum of three semi-quantitative histological grades: steatosis, graded from 0 [<5% liver fat] to grade 3 [>66% liver fat] lobular inflammation, graded from 0 [no foci of inflammation] to 3 [>4 foci per 200x field] hepatocellular ballooning, graded from 0 [no ballooning] to 2 [many cells/prominent ballooning] The "total" NAFLD activity score, a sum of the three components below, ranges from 0 to 8, with a higher score generally representing greater severity of NAFLD/nonalcoholic steatohepatitis. |
| Time Frame | change between baseline and 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| all participants with available biopsy data from both baseline and 12 month visits |
| Arm/Group Title | Tesamorelin | Placebo |
|---|---|---|
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin |
| Measure Participants | 19 | 24 |
| Mean (Standard Deviation) [score on a scale, NAFLD activity score] |
-0.16
(1.34)
|
0.13
(1.03)
|
| Title | Change in Alanine Aminotransferase (ALT) |
|---|---|
| Description | change (value at 12 months minus value at baseline) |
| Time Frame | change from baseline to 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| all participants with available data at both baseline and 12 month visits |
| Arm/Group Title | Tesamorelin | Placebo |
|---|---|---|
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin |
| Measure Participants | 21 | 24 |
| Mean (Standard Deviation) [units/liter (U/L)] |
-2
(11)
|
5
(15)
|
| Title | Change in Aspartate Aminotransferase (AST) |
|---|---|
| Description | change (value at 12 months minus value at baseline) |
| Time Frame | change from baseline to 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| all participants with available data at both baseline and 12 month visits |
| Arm/Group Title | Tesamorelin | Placebo |
|---|---|---|
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin |
| Measure Participants | 20 | 24 |
| Mean (Standard Deviation) [units/liter (U/L)] |
-2
(11)
|
-2
(4)
|
Adverse Events
| Time Frame | Adverse events reported herein are from the double-blind (tesamorelin vs. placebo) phase of the study which was 12 months in length as well as the subsequent open-label phase 6 months in length. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The primary analysis is from baseline to 12 months, during the "double-blind" phase. Adverse events from this phase are reported under the "Tesamorelin (Double-blind phase)" and "Placebo (Double-blind phase)" descriptors. 43 participants subsequently entered a 6 month open label phase during which all received tesamorelin. Data from this phase are not included in analysis, but Adverse Event data from the Open Label phase are included under the descriptor, "Open Label Tesamorelin Arm." | |||||
| Arm/Group Title | Tesamorelin (Double-blind Phase) | Placebo (Double-blind Phase) | Open Label Tesamorelin Arm | |||
| Arm/Group Description | tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. tesamorelin | placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months. Placebo: inactive substance that looks like tesamorelin | following the 12 month double-blind period, all subjects received open-label tesamorelin 2mg daily subcutaneously for 6 months. | |||
All Cause Mortality |
||||||
| Tesamorelin (Double-blind Phase) | Placebo (Double-blind Phase) | Open Label Tesamorelin Arm | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/31 (0%) | 0/30 (0%) | 1/43 (2.3%) | |||
Serious Adverse Events |
||||||
| Tesamorelin (Double-blind Phase) | Placebo (Double-blind Phase) | Open Label Tesamorelin Arm | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/31 (12.9%) | 2/30 (6.7%) | 3/43 (7%) | |||
| General disorders | ||||||
| Death sudden | 0/31 (0%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Hepatobiliary disorders | ||||||
| Hepatic Hematoma | 0/31 (0%) | 1/30 (3.3%) | 0/43 (0%) | |||
| Infections and infestations | ||||||
| Viral infection | 1/31 (3.2%) | 0/30 (0%) | 0/43 (0%) | |||
| Soft tissue infection | 0/31 (0%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Urosepsis | 1/31 (3.2%) | 0/30 (0%) | 0/43 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Drug overdose | 0/31 (0%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Nervous system disorders | ||||||
| Hemiplegia transient | 1/31 (3.2%) | 0/30 (0%) | 0/43 (0%) | |||
| Psychiatric disorders | ||||||
| Anxiety Depression | 0/31 (0%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Suicide attempt | 0/31 (0%) | 1/30 (3.3%) | 0/43 (0%) | |||
| Active suicidal ideation | 1/31 (3.2%) | 0/30 (0%) | 0/43 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pneumonia | 1/31 (3.2%) | 0/30 (0%) | 1/43 (2.3%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Tesamorelin (Double-blind Phase) | Placebo (Double-blind Phase) | Open Label Tesamorelin Arm | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 29/31 (93.5%) | 29/30 (96.7%) | 35/43 (81.4%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 1/31 (3.2%) | 2/30 (6.7%) | 0/43 (0%) | |||
| General disorders | ||||||
| Fatigue | 2/31 (6.5%) | 1/30 (3.3%) | 0/43 (0%) | |||
| Injection site bruising | 11/31 (35.5%) | 11/30 (36.7%) | 1/43 (2.3%) | |||
| Injection site induration | 3/31 (9.7%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Injection site itching | 4/31 (12.9%) | 1/30 (3.3%) | 0/43 (0%) | |||
| Injection site pain | 2/31 (6.5%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Injection site redness | 4/31 (12.9%) | 0/30 (0%) | 0/43 (0%) | |||
| Injection site stinging | 4/31 (12.9%) | 1/30 (3.3%) | 4/43 (9.3%) | |||
| Infections and infestations | ||||||
| Cellulitis | 0/31 (0%) | 1/30 (3.3%) | 2/43 (4.7%) | |||
| Pneumonia | 1/31 (3.2%) | 1/30 (3.3%) | 2/43 (4.7%) | |||
| Sinusitis | 2/31 (6.5%) | 3/30 (10%) | 0/43 (0%) | |||
| Tooth Infection | 2/31 (6.5%) | 1/30 (3.3%) | 1/43 (2.3%) | |||
| URTI (upper respiratory tract infection) | 5/31 (16.1%) | 5/30 (16.7%) | 3/43 (7%) | |||
| Viral infection | 1/31 (3.2%) | 2/30 (6.7%) | 1/43 (2.3%) | |||
| Injury, poisoning and procedural complications | ||||||
| Fall | 1/31 (3.2%) | 2/30 (6.7%) | 1/43 (2.3%) | |||
| Fracture | 3/31 (9.7%) | 1/30 (3.3%) | 0/43 (0%) | |||
| Pain post biopsy | 3/31 (9.7%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 7/31 (22.6%) | 5/30 (16.7%) | 4/43 (9.3%) | |||
| Alkaline phosphatase increased | 3/31 (9.7%) | 0/30 (0%) | 2/43 (4.7%) | |||
| Aspartate aminotransferase increased | 3/31 (9.7%) | 2/30 (6.7%) | 3/43 (7%) | |||
| Fasting blood glucose increased | 12/31 (38.7%) | 11/30 (36.7%) | 14/43 (32.6%) | |||
| Nonspecific abnormal findings on radiological and other examinations | 1/31 (3.2%) | 2/30 (6.7%) | 0/43 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Hyper LDL cholesterolemia | 3/31 (9.7%) | 2/30 (6.7%) | 0/43 (0%) | |||
| Hypercholesterolemia | 3/31 (9.7%) | 1/30 (3.3%) | 1/43 (2.3%) | |||
| Hypertriglyceridemia | 5/31 (16.1%) | 3/30 (10%) | 2/43 (4.7%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 3/31 (9.7%) | 3/30 (10%) | 1/43 (2.3%) | |||
| Myalgia | 2/31 (6.5%) | 0/30 (0%) | 1/43 (2.3%) | |||
| Nervous system disorders | ||||||
| Paresthesia | 2/31 (6.5%) | 2/30 (6.7%) | 0/43 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Rash | 1/31 (3.2%) | 0/30 (0%) | 2/43 (4.7%) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Steven Grinspoon, MD |
|---|---|
| Organization | Massachusetts General Hospital |
| Phone | 617-724-9109 |
| sgrinspoon@mgh.harvard.edu |
- 1U01AI115711
- U01AI115711