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.
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
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)
Parallel
Metabolic surgery
Procedure/SurgeryPatients receive either RYGB or SG. The surgical risk, differential impact of each procedure on body weight and other obesity-related diseases, presence of other medical and mental problems, patient's behavioral factors (e.g., postoperative compliance, active smoking), medications, and goals will be considered when the patient and local medical team make a shared decision about the most appropriate surgical procedure
Incretin-Based Therapy
DrugThree incretin-based medications that have been approved for treatment of obesity including liraglutide, semaglutide, or tirzepatide will be used in the nonsurgical group. Any of these 3 medications (in the injection or oral from) based on availability in each country, access, and clinical indications can be used. If possible, patients will be placed on high-dose tirzepatide (Mounjaro or Zepbound 15 mg once weekly injection) or high-dose semaglutide (Wegovy 2.4 mg once weekly injection or Ozempic 2 mg once weekly injection). Other acceptable, less preferrable, options: liraglutide (Saxenda or Victoza), semaglutide tablet (Rybelsus), or lower dose of tirzepatide and semaglutide injections.
Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy.
Development of hepatic decompensation events including ascites (requiring treatment including diuretics), spontaneous bacterial peritonitis, hepatic encephalopathy (requiring treatment or hospitalization), or bleeding esophageal varices, and all-cause mortality will be counted as a treatment failure with no need for repeating liver biopsy.
MASH resolution in the repeat liver biopsy
MASH resolution defined as no hepatocyte ballooning (score of 0 according to the NASH CRN criteria), no more than mild residual inflammatory cells (score of 0 or 1), without worsening of liver fibrosis stage in the repeat liver biopsy
MASH resolution and fibrosis improvement in the repeat liver biopsy
Presence of both MASH resolution and fibrosis improvement in the repeat liver biopsy
Fibrosis progression in the repeat liver biopsy
Defined as worsening of at least 1 fibrosis stage of the Kleiner fibrosis classification in the repeat liver biopsy among patients who did not have F4 in the baseline liver biopsy
Average Weight loss percentage
Mean percentage weight loss from baseline
MASLD-related histopathologic end points
* Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification, regardless of changes in MASH severity * Progression to cirrhosis (F4) in repeat liver biopsy among patients who did not have F4 in the baseline liver biopsy * Mean and change from baseline in NAFLD Activity Score * Reduction in NAFLD Activity Score by at least 1, 2, or 3 points * Histopathological changes in severity of steatosis, inflammation, hepatocyte ballooning, and fibrosis * Histopathological changes in modified Ishak fibrosis score * Histopathological changes in features of regression (Beijing classification, P-I-R fibrosis quality)
MASLD-related laboratory end points
Mean and change from baseline in ALT, AST, Alkaline phosphatase, bilirubin, platelet count, eGFR, and FIB-4
MASLD-related liver scan end points
Change in liver stiffness in elastography (based on the same device that was used at baseline)
MASLD-related clinical end points
Development of adverse clinical outcomes including development of ascites or hydrothorax (requiring treatment including diuretics), hepatic encephalopathy (requiring treatment or hospitalization), bleeding esophageal varices, liver-related mortality, and all-cause mortality as a composite and individual end points
Click on the lead sponsor to view all of their trials.