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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Obesity; Fatty Liver; Liver Fat; Obesity, Abdominal; Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Tesamorelin; Drug: Identical Placebo

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Takara L Stanley, MD; Phone Number: 617-724-9109; Email: tstanley@mgh.harvard.edu
• Study Contact Backup: Name: Kathleen E. Corey, MD, MPH; Email: kcorey@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men and women 18-65yo
2. Body mass index (BMI) ≥ 30kg/m2, or, for participants with known steatohepatitis, BMI ≥ 25kg/m2
3. 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)
4. 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.
5. For females ≥50yo, negative mammogram within 1 year of baseline
6. If use of vitamin E ≥400 international units daily, stable dose for ≥6 mos
7. 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:

1. 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
2. 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).
3. Use of any specific pharmacological treatments for NAFLD/nonalcoholic steatohepatitis except vitamin E
4. 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.
5. Chronic systemic corticosteroid use in the ≤6 months prior to the baseline visit
6. Chronic use of Actigall, methotrexate, amiodarone, or tamoxifen
7. Known diagnosis of alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis
8. Use of growth hormone or growth hormone releasing hormone within the past 6 months
9. Change in lipid lowering or anti-hypertensive regimen within 2 months of screening
10. Hemoglobin < 10.0 g/dL or Creatinine >1.5mg/dL
11. Active malignancy
12. For men, history of prostate cancer or evidence of prostate malignancy by prostate specific antigen (PSA) > 5 ng/mL
13. Severe chronic illness judged by the investigator to present a contraindication to participation
14. History of hypopituitarism, head irradiation or any other condition known to affect the GH axis
15. Use of physiologic testosterone (men) or estrogen or progesterone (women) unless stable use for a year or more prior to study entry
16. Routine magnetic resonance imaging (MRI) exclusion criteria such as the presence of a pacemaker or cerebral aneurysm clip
17. 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)
18. For women, positive urine pregnancy test (hCG), trying to achieve pregnancy, or breastfeeding
19. For women able to become pregnant, unwillingness to use an acceptable form of birth control during the study.
20. Known hypersensitivity to tesamorelin or mannitol
21. Contraindication to receiving beta-blocker or nitroglycerin (which are part of the coronary angiography)
22. 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
23. Active consideration for a procedure or treatment that involves significant radiation exposure as defined above in the 12 months following randomization
24. Not willing or able to adhere to dose schedules and required procedures per protocol
25. Judged by the investigator to be inappropriate for the study for other reasons not detailed above.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2019
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: December 13, 2017
• First Submitted That Met QC Criteria: December 13, 2017
• First Posted (Actual): December 18, 2017

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 29, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: obesity; fatty liver; tesamorelin
• Additional Relevant MeSH Terms: Digestive System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Liver Diseases; Obesity; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity, Abdominal; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Growth Substances; Hormones; Growth Hormone-Releasing Hormone; Tesamorelin
• Other Study ID Numbers: R01DK114144 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Final Research Data, with all patient identifiers removed, will be available to other researchers through request to the PI. Because information contained in the final research data will include multiple demographic and biological variables that could potentially be used in concert to identify participants, it will be shared only under a Data Sharing Agreement that includes (1) a commitment to using the data only for research purposes and not to identify any individual participant and (2) a commitment to destroying or returning the data after analyses are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No