Fibrosis Lessens After Metabolic Surgery

NCT06374875 | Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: 24-213
• Study Type: interventional
• Target: 120
• Locations: 13 countries
• Sites: 22

Brief Summary

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.

Conditions

Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD); Non-Alcoholic Fatty Liver Disease; Metabolic Dysfunction-Associated Steatohepatitis (MASH); Liver Fibrosis; Obesity

Outcome Measures

Primary Outcomes (1)

• 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.

  Through study completion, 2 years

Secondary Outcomes (5)

• MASH resolution in the repeat liver biopsy

  Through study completion, 2 years

• MASH resolution and fibrosis improvement in the repeat liver biopsy

  Through study completion, 2 years

• Fibrosis progression in the repeat liver biopsy

  Through study completion, 2 years

• Average Weight loss percentage

  Through study completion, 2 years

• Disease-specific Quality of Life (QoL)

  Through study completion, 2 years

Other Outcomes (18)

• MASLD-related histopathologic end points

  Through study completion, 2 years

• MASLD-related laboratory end points

  Through study completion, 2 years

• MASLD-related liver scan end points

  Through study completion, 2 years

Study Arms (2)

Metabolic Surgery

ACTIVE COMPARATOR

FLAMES will examine the class effect (not the specific procedure effect) of metabolic surgery. The study is not intended to compare Roux-en-Y Gastric Bypass (RYGB) vs Sleeve Gastrectomy (SG) head-to-head. RYGB and SG constitute one group as a metabolic surgery group. Assignment of RYGB or SG is not based on a randomized design. Each patient and surgical team will make a shared decision about the most appropriate surgical procedure.

Procedure: Metabolic surgery

Incretin-Based Therapy

ACTIVE COMPARATOR

Three incretin-based medications that have been approved for treatment of obesity including liraglutide, semaglutide, or tirzepatide will be used in the nonsurgical group. The FLAMES will examine the class effect (not the specific drug effect) of incretin-based therapies. The study is not intended to compare semaglutide vs tirzepatide vs liraglutide head-to-head.

Drug: Incretin-Based Therapy

Interventions

Metabolic surgery PROCEDURE

Patients 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

Also known as: Bariatric surgery, Roux-en-Y Gastric Bypass (RYGB), Sleeve Gastrectomy (SG)

Metabolic Surgery

Incretin-Based Therapy DRUG

Three 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.

Also known as: Glucagon-like Peptide-1 Receptor Agonist

Incretin-Based Therapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Entry into the study would require that the patient:
• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Ali Aminian: lead
• Sobia Laique, MD: collaborator

Study Sites (22)

Banner Health Center

Phoenix, Arizona, 85006, United States

NOT YET RECRUITING

Indiana University

Indianapolis, Indiana, 46202, United States

NOT YET RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

NOT YET RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

Hospital Alemão Oswaldo Cruz

São Paulo, Brazil

RECRUITING

McGill University

Montreal, Canada

NOT YET RECRUITING

Turku University Hospital

Turku, Finland

NOT YET RECRUITING

Sri Aurobindo Institute of Medical Sciences

Indore, India

NOT YET RECRUITING

The Digestive Health Institute

Mumbai, India

NOT YET RECRUITING

University College Dublin

Dublin, Ireland

NOT YET RECRUITING

Università Cattolica del Sacro Cuore

Milan, Italy

NOT YET RECRUITING

Sapienza Università di Roma

Roma, Italy

NOT YET RECRUITING

Kuwait University

Kuwait City, Kuwait

NOT YET RECRUITING

Instituto Nacional de Ciencias Médicas y Nutrición Salvador

Mexico City, Mexico

NOT YET RECRUITING

Hospital Clínic Barcelona

Barcelona, Spain

NOT YET RECRUITING

Linköping University

Linköping, Sweden

NOT YET RECRUITING

Örebro University

Örebro, Sweden

NOT YET RECRUITING

Clarunis Universitäres

Basel, Switzerland

NOT YET RECRUITING

Hôpitaux universitaires de Genève

Geneva, Switzerland

NOT YET RECRUITING

Nuffield Health Bristol Hospital

Bristol, United Kingdom

NOT YET RECRUITING

King's College Hospital

London, United Kingdom

NOT YET RECRUITING

Queen Mary University

London, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Obesity

Interventions

Bariatric Surgery; Gastric Bypass

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Bariatrics; Obesity Management; Therapeutics; Surgical Procedures, Operative; Gastroenterostomy; Anastomosis, Surgical; Digestive System Surgical Procedures

Study Officials

• Ali Aminian, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Awwab F Hammad, MD

CONTACT

+1 216 444 5022; hammada4@ccf.org

Chytaine Hall

CONTACT

216-445-3983; hallc1@ccf.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Patients and investigators will not be blinded to treatment assignment. The treatment assignment will remain unknown until the patient is randomized after meeting all eligibility requirements. Pathologists who report the liver biopsies (to assess the primary end point of study) are blinded to treatment assignment
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of Bariatric and Metabolic Institute

Model Details: Patients will be randomized in a 1:1 ratio into 1 of the 2 arms using a computer-generated randomization plan, stratified to ensure that there are equal number of patients with/without T2DM and with/without F4 (cirrhosis) according to the baseline liver biopsy in each treatment group (surgical group vs non-surgical group). The participant sites are regrouped into three geographic regions. All patients in each region will be randomized separately to have equal number of patients with/without T2DM and with/without F4 in each treatment group in each region.

Study Record Dates

• First Submitted: April 16, 2024
• First Posted: April 19, 2024
• Study Start: July 11, 2024
• Primary Completion (Estimated): May 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: August 22, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share

Locations

GB (3); CA (1); ME (1); US (4); IN (2); BR (1); IE (1); ES (1); SE (2); FI (1); CH (2); KU (1); IT (2)