Growth Hormone Releasing Hormone Analog to Improve Nonalcoholic Fatty Liver Disease and Associated Cardiovascular Risk

Study Overview
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Brief Summary
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Nonalcoholic fatty liver disease (NAFLD) is common in individuals with obesity and is a significant threat to public health, because it can lead to impaired liver function and liver failure. Growth hormone is a hormone produced in the pituitary gland that helps regulate metabolism and growth. Individuals with obesity, on average, secrete less growth hormone than individuals without obesity. There are data to suggest that growth hormone may help to reduce the amount of fat in the liver, and may also reduce inflammation in the liver, both of which would be helpful to individuals with NAFLD. The purpose of this study is to investigate whether treatment with a drug called tesamorelin, which is a growth hormone releasing hormone analogue, will decrease liver fat and improve liver inflammation and scarring in obese individuals with NAFLD.

Official Title
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Growth Hormone Releasing Hormone Analog to Improve Nonalcoholic Fatty Liver Disease and Associated Cardiovascular Risk

Conditions
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Non-Alcoholic Fatty Liver Disease, Obesity, Obesity, Abdominal, Liver Fat, Fatty Liver

Intervention / Treatment
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* Drug: Tesamorelin
* Drug: Identical Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 18-65yo Body mass index (BMI) ≥ 30kg/m2, or, for participants with known steatohepatitis, BMI ≥ 25kg/m2 Hepatic steatosis as demonstrated by either a) Grade 1+ steatosis on a liver biopsy performed within 12 months of the baseline visit, without >10% reduction in body weight or addition of medications to treat fatty liver, or b) liver fat fraction ≥5% on hydrogen-magnetic resonance spectroscopy (1H-MRS) Hepatitis C antibody and Hepatitis B surface antigen negative. Subjects without known history of Hepatitis C or Hepatitis C treatment who have a positive Hepatitis C antibody but a negative hepatitis C viral load will also be eligible. For females ≥50yo, negative mammogram within 1 year of baseline If use of vitamin E ≥400 international units daily, stable dose for ≥6 mos Up to date with colon cancer screening recommended by the participant's primary care physician, using whatever methodology the primary physician recommends. This will be ascertained by self-report. (If a participant does not have a primary care physician, we will discuss that colon cancer screening is recommended, typically starting at age 50y, and refer the participant to primary care through Partners if s/he desires.) Exclusion Criteria: Heavy alcohol use defined as consumption of > 20 grams daily for women or > 30 grans daily for men for at least 3 consecutive months over the past 5 years assessed using the Lifetime Drinking History Questionnaire Known diagnosis of diabetes, use of any anti-diabetic medications (including thiazolidinediones or metformin), fasting glucose >126mg/dL, or hemoglobin A1c (HbA1c) ≥6.5%. Participants with stable use of metformin ≥6 months will be permitted if it is being used for pre-diabetes or another non-diabetes indication (e.g., PCOS). Use of any specific pharmacological treatments for NAFLD/nonalcoholic steatohepatitis except vitamin E Known cirrhosis, Child-Pugh score ≥7, stage 4 fibrosis on biopsy, or clinical evidence of cirrhosis or portal hypertension on imaging or exam. If a subject is not known to be cirrhotic at screen but is found to be cirrhotic based on the results of liver biopsy at baseline, this subject will be referred to a hepatologist for clinical care and will be excluded from further participation in the study. Chronic systemic corticosteroid use in the ≤6 months prior to the baseline visit Chronic use of Actigall, methotrexate, amiodarone, or tamoxifen Known diagnosis of alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis Use of growth hormone or growth hormone releasing hormone within the past 6 months Change in lipid lowering or anti-hypertensive regimen within 2 months of screening Hemoglobin < 10.0 g/dL or Creatinine >1.5mg/dL Active malignancy For men, history of prostate cancer or evidence of prostate malignancy by prostate specific antigen (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 magnetic resonance imaging (MRI) exclusion criteria such as the presence of a pacemaker or cerebral aneurysm clip Weight loss surgery within 1 year before baseline. Weight loss surgery more than 1 year prior to baseline visit is permissible as long as no active weight loss (<10% decrease in weight over past 6 months) For women, positive urine pregnancy test (hCG), trying to achieve pregnancy, or breastfeeding For women able to become pregnant, unwillingness to use an acceptable form of birth control during the study. Known hypersensitivity to tesamorelin or mannitol Contraindication to receiving beta-blocker or nitroglycerin (which are part of the coronary angiography) Significant radiation exposure, including any history of radiation therapy, or any of the following in the 12 months prior to randomization: a) more than 2 percutaneous coronary interventions; b) more than 2 myocardial perfusion studies; 3) more than 2 computed tomography angiograms Active consideration for a procedure or treatment that involves significant radiation exposure as defined above in the 12 months following randomization Not willing or able to adhere to dose schedules and required procedures per protocol Judged by the investigator to be inappropriate for the study for other reasons not detailed above.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo controlled phase for first 12 months, followed by open-label phase for 6 months during which all participants receive active medication (tesamorelin)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tesamorelin<br>tesamorelin (brand name Egrifta) 2mg daily given subcutaneously | Drug: Tesamorelin<br>* Tesamorelin F4 formulation 1.4mg daily<br>* Other names: Egrifta, TH9507, Growth Hormone Releasing Hormone Analog;|
| Placebo Comparator: Placebo<br>identical placebo given subcutaneously daily | Drug: Identical Placebo<br>* Placebo injection daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver Fat Content | Liver Fat Content as measured by hydrogen-magnetic resonance spectroscopy | change from baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAFLD Activity Score | NAFLD Activity Score (NAS, scored between 0-8) from liver biopsy | change from baseline to 12 months | 
| Post-prandial hepatic de novo lipogenesis | hepatic de novo lipogenesis as measured by stable isotope methods | change from baseline to 12 months | 
| Non-high density lipoprotein (Non-HDL) Cholesterol |  | change from baseline to 12 months | 
| C-reactive protein |  | change from baseline to 12 months | 
| Fibrosis Score | fibrosis score from liver biopsy | change from baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tesamorelin, obesity, fatty liver