Non-Alcoholic Fatty Liver Disease, the HEpatic Response to Oral Glucose, and the Effect of Semaglutide (NAFLD HEROES)

NCT03884075 | Recruiting Phase 2

• 2 other identifiers: 19007219-DK-0072
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

Background: In non-alcoholic fatty liver disease (NAFLD), fat accumulates in the liver and can cause damage. Researchers want to learn what causes the damage NAFLD, and to see if a medication can help. Objective: To find out how the liver in people with NAFLD responds to feeding, and how this relates to their response to the drug semaglutide. Eligibility: People with NAFLD and healthy volunteers ages 18 and older Design: Participants will be screened with: Medical history Physical exam Blood tests Imaging: A machine will take pictures of the participant s body. Within 2-8 weeks of enrollment, participants will stay in the clinic for several days. This includes: Blood, urine, heart, and imaging tests For NAFLD participants only: A needle-like device will remove a small biopsy of the liver and fatty tissue. Participants will be alone in a special room for 5 hours. They will breathe through a tube under the nostrils. They will have blood drawn several times. The baseline visit concludes participation for healthy volunteers but NAFLD participants will contine. About 6 weeks after discharge, participants will stay in the clinic again and repeat the tests. They will get their first semaglutide dose by injection. Participants will have visits weeks 1, 2, 4, 8, 12, 16, 20, and 24 of treatment. Visits include blood tests. Participants will inject semaglutide once a week at home. At week 30, participants will stay in the clinic again and repeat the tests. Participants will have a final visit 12 weeks after stopping treatment. This includes blood and urine tests. ...

Conditions

Non-Alcoholic Steatohepatitis; Non-Alcoholic Fatty Liver Disease

Keywords

Non-Alcoholic Steatohepatitis (NASH); Steatosis; Caloric Load

Outcome Measures

Primary Outcomes (3)

• Histological Improvement

  \>= point decrease in NAFLD activity score (range 0-8, high scores indicate more activity)

  30 weeks

• Clinical Improvement

  Reduction of liver fat content (measure with 1H-magnetic resonance spectroscopy) by \>= 25% and reduction of ALT by \>=25% or normalization of ALT

  30 weeks

• Change in hepatic gene expression

  Change in hepatic gene expression for biopsies performed at baseline and 2 hours after an oral 75g glucose load

  2 hours after an oral 75g glucose load

Study Arms (3)

Arm A: Steatosis

EXPERIMENTAL

Participants with steatosis on baseline biopsy

Drug: Semaglutide

Arm B: NASH

EXPERIMENTAL

Participants with NASH on baseline biopsy

Drug: Semaglutide

Arm C: Healthy

NO INTERVENTION

Healthy Volunteers

Interventions

Semaglutide DRUG

Semaglutide injection once weekly

Arm A: Steatosis; Arm B: NASH

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female Aged \>= 18 years of age.
• Histological evidence of hepatic steatosis on a liver biopsy within 12 months OR evidence of fatty liver disease, as documented by imaging (ultrasound, CT, MRI, MRI-PDFF, MR spectroscopy, or Fibroscan CAP \>= 285 db/M25) within 12 months.
• Estimated average alcohol consumption \< 30 g/d for men or \< 20 g/d for women in the 6 months prior to enrollment and no binge-drinking behavior.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Presence of NAFLD (steatosis grade greater than or equal to 1 on NASH-CRN scoring scale) on baseline admission liver biopsy.
• Liver fat content greater than or equal to 10% by 1H-MRS on initial admission.

You may not qualify if:

• Pregnant or breast-feeding
• Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who were treated successfully for HCV and achieved sustained virological response can be eligible for enrollment \> 18 months after treatment cessation. Patients receiving antiviral therapy are ineligible.
• HIV infection.
• Concomitant liver disease such as autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson s disease, alpha-1 antitrypsin deficiency, hereditary hemochromatosis.
• Presence of definite or probable drug-induced liver injury. In the case of lipid-lowering, anti-hypertensive or anti-diabetic medications that are suspected to cause aminotransferase elevation, patients will be eligible if treatment is associated with stable enzyme levels for at least 6 months.
• Decompensated advanced liver disease, defined as direct bilirubin \> 0.5 g/dL, PT \> 18 , albumin \< 3 g/dL, MELD score \> 12 (applicable only in patients without Gilbert s syndrome), or history of ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis or liver transplant
• Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen
• Uncontrolled hypo- or hyperthyroidism.
• Thyroid nodules with ultrasonographic features suggestive of an increased risk of thyroid cancer per radiologist reporting (hypoechoic, microcalcifications, twinkling on B flow imaging, central vascularity, irregular margins, incomplete halo, nodule taller than wide and documented enlargement of a nodule), or nodules associated with an abnormal TSH (0.4 to 5 mU/L).
• Active coronary artery disease, defined as persistent angina pectoris, reversible ischemia on cardiac stress test or imaging, or the presence of significant coronary artery disease on imaging or catheterization. Patients with coronary artery disease that was treated by angioplasty or bypass surgery may be eligible if they have no evidence of active disease \>= 1 year after intervention, can safely stop antiplatelet and anticoagulant medications before the performance of invasive procedures, and have adequate ventricular function as assessed by echocardiography or cardiology consultation. These patients will require cardiology consultation and clearance prior to enrollment.
• Congestive heart failure.
• Chronic kidney disease, with creatinine clearance \< 60 ml/min or eGFR \< 60/ml/min/m(2).
• Uncontrolled diabetes mellitus with HbA1c \> 9% will exclude subjects. Patients with diabetes may be enrolled only if they have HbA1c \<=9%, have been on stable therapy with lifestyle and/or metformin for at least 3 months prior to enrollment, and are not foreseen to require change of antidiabetic medication or dose during the trial.
• Use of insulin, sulfonylurea agents, thiazolidinediones, SGLT2 inhibitors, GLP-1 receptor agonists or DPP-4 inhibitors unless discontinued greater than or equal to 3 months before enrollment.
• Contraindication or inability to perform a liver biopsy.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Fatty Liver

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Study Officials

• Yaron Rotman, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yaron Rotman, M.D.

CONTACT

(301) 451-6553; rotmanyaron@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2019
• First Posted: March 21, 2019
• Study Start: July 24, 2019
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): October 2, 2026
• Last Updated: May 12, 2026

Record last verified: 2026-05-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: IPD will shared at the time of publication or 6 months after publication.
• Access Criteria: Data will be shared through: @@@@@@@@@@@@ An NIH-funded or approved public repository. Insert name or names: NIDDK repository or a similar database.

Locations

US (1)