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FLAMES Study: Metabolic Surgery or Incretin-Based Therapy for Liver Fibrosis

This study, called FLAMES, is for people with obesity, liver fibrosis (scarring of the liver), and MASH (Metabolic Dysfunction-Associated Steatohepatitis), which is a severe form of MASLD (Metabolic Dysfunction-associated Steatotic Liver Disease, formerly NAFLD). It compares two ways to improve liver health: metabolic surgery (like RYGB or SG) or treatment with incretin-based medications (liraglutide, semaglutide, or tirzepatide). The goal is to see if either treatment can reduce liver fibrosis by at least one stage and prevent MASH from getting worse over two years. You might be able to join if you are 18-75 years old, eligible for metabolic surgery, and have insurance coverage for it.

Study design
This is a randomized, controlled study with 120 participants. You would be assigned to either metabolic surgery or incretin-based therapy, and the doctors evaluating your liver biopsy results won't know which treatment you received.
What's involved
You would undergo a baseline liver biopsy and then receive either metabolic surgery or incretin-based therapy for two years. A repeat liver biopsy will be performed at the end of the study.
Compensation
Not stated in the trial record.
Follow-up
Participants will be followed through study completion, which is 2 years.

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NCT06374875

Fibrosis Lessens After Metabolic Surgery

Recruiting
PHASE4Ages 18–75InterventionalTreatment
The Cleveland Clinic
~120 participants
Updated 2026-07-31 on ClinicalTrials.gov
What's tested:Metabolic surgeryIncretin-Based Therapy

At a glance

Recruiting sites
2 of 22 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy.
Measured over Through study completion, 2 years

Conditions

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

Explore related trials

Liver FibrosisNonalcoholic SteatohepatitisObesity

Where it's being run

22 sites across 16 states
United Kingdom3
India2
Italy2
Sweden2
Switzerland2
Arizona1
Indiana1
Minnesota1

Study leadership

  • Ali Aminian, MD · PRINCIPAL_INVESTIGATOR · The Cleveland Clinic

Who to contact

Awwab F Hammad, MD
[email protected]
+1 216 444 5022
Email the study team

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Do you actually qualify for this trial?

Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.

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Eligibility criteria

Inclusion

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 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%. 9. 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)

Exclusion

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 2. Weight change \>10% within 6 months prior to the first study visit or prior to the historical liver biopsy 3. Treatment with semaglutide, tirzepatide, or liraglutide (for obesity or for T2DM) \<90 days before the first study visit.
Patients receiving treatment for hypothyroidism can be included if their thyroid hormone replacement dose has been stable for at least 3 months.
Patients whose TSH is outside the rang but they have normal levels of thyroid hormones can be included. 33. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 34. Evidence or history of ascites or spontaneous bacterial peritonitis that require(d) treatment
Ruling out clinically significant portal hypertension is particularly important in patients with a liver stiffness ≥20 kPa or with a platelet count \<150,000 per μL or with a (historical) liver biopsy showing cirrhosis.
A subset of patients without having upper endoscopy and liver duplex ultrasound can be eligible for enrollment if their:
liver stiffness (by transient elastography using FibroScan®) is between 12 and 15 kPa and their platelet count is \>150,000 per μL, or
a (historical) liver biopsy showing absence of cirrhosis, or
a (historical) HVPG \< 5 mmHg 57. Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites
F0 in de novo biopsy; Enrollment cap of 20% for F1 in de novo biopsy.
F0 and F1 in historical liver biopsy
Absence of all three components of MASH (steatosis, hepatocyte ballooning, and lobular inflammation) in patients with F1, F2, and F3
Absence of steatosis (\<5%) in patients with F4
Diagnosis other than MASH

What this trial measures

  • Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy.Through study completion, 2 years

    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.