Fibrosis Lessens After Metabolic Surgery

What this study is about

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), a major global public health concern, is commonly associated with obesity, diabetes, and dyslipidemia. MASLD is currently the most common cause of chronic liver disease affecting about 80% of people with obesity, ranging from simple fat deposits in the liver to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cellular injury, advanced fibrosis, cirrhosis, or hepatocellular carcinoma. Patients with MASH are also at risk for cardiovascular disease and mortality. There is no universally approved medication for MASH. Weight loss remains the cornerstone of MASH treatment. Patients meeting the inclusion and exclusion criteria and who give informed consent will be enrolled in the trial and undergo the baseline liver biopsy (if none available). Approximately 120 patients with MASH and liver fibrosis (F1-F4 in baseline liver biopsy) will be randomized in a 1:1 ratio to metabolic surgery or medical treatment (incretin-based therapies ± other medical therapies for MASH) and followed for 2 years at which time a repeat liver biopsy will be performed for the assessment of the primary end point.

Who can join (things the study team will check)

✅ You may be able to join if…

• Is a candidate for general anesthesia
• Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines
• Has insurance coverage for metabolic surgery (the requirements may vary in each country)
• Is ≥18 and ≤75 years old at the time of signing the informed consent
• Has a BMI ≥35 and ≤70 kg/m2 at the time of first study visit
• FIB-4 ≥ 1.3
• At least one of the following 5 criteria suggesting presence of advanced fibrosis:
  • LSM ≥ 12 kPa by VCTE using FibroScan®
  • LSM ≥ 12 kPa by SWE
  • LSM ≥ 1.7 m/s by ARFI
  • LSM ≥ 3.63 kPa MRE
  • ELF score ≥ 9.8
• Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication (including insulin but not semaglutide or tirzepatide or liraglutide) for at least 3 months prior to entry, with glycated hemoglobin (HbA1c) ≤12%.
• Self-reported stable weight in 6 months before the first study visit (no weight loss >10% within 6 months prior to the first study visit) a. In patients with a historical noninvasive tests or liver biopsy, weight loss of no more than 10% is allowed from 6 months prior to the historical tests until the first study visit
• Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study
• Can understand the options and comply with the requirements of each arm, including one liver biopsy performed during the screening period (if no adequate biopsy within 12 months before screening is available) and one liver biopsy after 2-years
• Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential.
• Women of childbearing age must agree to use reliable method of contraception for 2 years 8.2 Exclusion Criteria Patients who meet the following criteria will be excluded from the study:
• Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic):
  • Hepatitis B as detected by presence of hepatitis B surface antigen (HBsAg)
  • Hepatitis C as detected by presence of hepatitis C virus (HCV) RNA (in case the screening test for hepatitis C is positive, the confirmative test is decisive)
  • Autoimmune liver disease as diagnosed by antibodies or compatible liver histology
  • Primary biliary cirrhosis as defined by the presence of at least 2 criteria (elevated alkaline phosphatase, presence of anti-mitochondrial antibody, and histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts)
  • Primary sclerosing cholangitis
  • Wilson's disease as diagnosed by low ceruloplasmin or compatible liver histology
  • Alpha-1-antitrypsin deficiency as diagnosed by alpha1-antitrypsin level or liver histology
  • Hemochromatosis as diagnosed by HFE mutations (C282Y, H63D), ferritin and transferrin saturation levels, or presence of 3+ or 4+ stainable iron on liver biopsy
  • Drug-induced liver disease diagnosed by medical history
  • Known bile duct obstruction
  • Suspected or proven liver cancer
• Weight change >10% within 6 months prior to the first study visit or prior to the historical liver biopsy
• Treatment with semaglutide, tirzepatide, or liraglutide (for obesity or for T2DM) <90 days before the first study visit.
  • However, patients are allowed to participate if they have been on a low dose (or are on older generation GLP-1 agonists) and have lost less than 10% of their body weight since starting the medication.
• Type 1 diabetes or autoimmune diabetes
• Known cases of human immunodeficiency virus infection
• Prior bariatric and metabolic surgery of any kind
  • Reversed procedures such as gastric band or intragastric balloon that have been removed at least 3 months prior to the first study visit are allowed.
• Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery

+ 52 more criteria — see the full checklist in the app.

Where this trial is running

• Banner Health Center, Phoenix, Arizona, United States
• Indiana University, Indianapolis, Indiana, United States
• Mayo Clinic, Rochester, Minnesota, United States
• Cleveland Clinic, Cleveland, Ohio, United States
• Hospital Alemão Oswaldo Cruz, São Paulo, Brazil
• McGill University, Montreal, Canada
• Turku University Hospital, Turku, Finland
• Sri Aurobindo Institute of Medical Sciences, Indore, India
• The Digestive Health Institute, Mumbai, India
• University College Dublin, Dublin, Ireland
• Università Cattolica del Sacro Cuore, Milan, Italy
• Sapienza Università di Roma, Roma, Italy

+ 10 more sites.

Who to contact

Awwab F Hammad, MD · +1 216 444 5022 · hammada4@ccf.org

It's completely normal to call and ask questions before deciding anything. Mention the study ID: NCT06374875.