Tesamorelin Effects on Liver Fat and Histology in HIV

NCT02196831 | Completed Results DMC

• 2 other identifiers: 1U01AI115711U01AI115711
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 2

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.

Conditions

Human Immunodeficiency Virus (HIV); Nonalcoholic Fatty Liver Disease (NAFLD); Nonalcoholic Steatohepatitis (NASH)

Keywords

Human immunodeficiency virus (HIV); Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH); Growth hormone releasing hormone; tesamorelin

Outcome Measures

Primary Outcomes (1)

• Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy

  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.

  change between baseline and 12 months

Secondary Outcomes (3)

• Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score

  change between baseline and 12 months

• Change in Alanine Aminotransferase (ALT)

  change from baseline to 12 months

• Change in Aspartate Aminotransferase (AST)

  change from baseline to 12 months

Study Arms (2)

Tesamorelin

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

tesamorelin DRUG

Also known as: Egrifta

Tesamorelin

Placebo DRUG

inactive substance that looks like tesamorelin

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

National Institutes of Health

Bethesda, Maryland, 20892, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (4)

• Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, Pan CS, Aepfelbacher J, Buckless C, Tsao A, Kellogg A, Branch K, Lee H, Liu CY, Corey KE, Chung RT, Torriani M, Kleiner DE, Hadigan CM, Grinspoon SK. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019 Dec;6(12):e821-e830. doi: 10.1016/S2352-3018(19)30338-8. Epub 2019 Oct 11.

  PMID: 31611038 RESULT

• Fourman LT, Stanley TL, Billingsley JM, Sui SJH, Feldpausch MN, Boutin A, Zheng I, McClure CM, Corey KE, Torriani M, Kleiner DE, Hadigan CM, Chung RT, Grinspoon SK. Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach. Sci Rep. 2021 May 18;11(1):10485. doi: 10.1038/s41598-021-89966-y.

  PMID: 34006921 DERIVED

• Stanley TL, Fourman LT, Wong LP, Sadreyev R, Billingsley JM, Feldpausch MN, Zheng I, Pan CS, Boutin A, Lee H, Corey KE, Torriani M, Kleiner DE, Chung RT, Hadigan CM, Grinspoon SK. Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease. Clin Infect Dis. 2021 Aug 16;73(4):621-630. doi: 10.1093/cid/ciab019.

  PMID: 33852720 DERIVED

• Stanley TL, Fourman LT, Zheng I, McClure CM, Feldpausch MN, Torriani M, Corey KE, Chung RT, Lee H, Kleiner DE, Hadigan CM, Grinspoon SK. Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e520-e533. doi: 10.1210/clinem/dgaa792.

  PMID: 33125080 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Non-alcoholic Fatty Liver Disease

Interventions

tesamorelin

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases

Results Point of Contact

• Title: Steven Grinspoon, MD
• Organization: Massachusetts General Hospital

sgrinspoon@mgh.harvard.edu

617-724-9109

Study Officials

• Steven K Grinspoon, MD

  MGH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: July 18, 2014
• First Posted: July 22, 2014
• Study Start: July 1, 2015
• Primary Completion: January 16, 2019
• Study Completion: July 24, 2019
• Last Updated: January 27, 2020
• Results First Posted: January 13, 2020

Record last verified: 2020-01

Locations

US (2)