Fibrosis Lessens After Metabolic Surgery

FLAMES (Fibrosis Lessens After Metabolic Surgery) is a 2-arm randomized, controlled, pathologist-blinded multicenter study with 2 parallel groups of patients with MASH, liver fibrosis, and obesity who will either receive metabolic surgery or incretin-based therapies (semaglutide [injection or oral], tirzepatide [injection], or liraglutide [injection]) for 2 years to assess the effects of advanced surgical and medical therapies in liver histology in patients with obesity, biopsy-proven MASH, and liver fibrosis. With genuine uncertainty in the expert medical community and literature over which treatment will result in a greater improvement in histopathological features of MASH and liver fibrosis, the investigators aim to compare metabolic surgery and incretin-based therapies head-to-head.

Adult patients with BMI between 35 - 60 kg/m^2, Fibrosis-4 (FIB-4) index ≥ 1.3, liver stiffness measure (LSM) ≥ 12 kPa by vibration-controlled transient elastography (VCTE) using FibroScan (or similar non-invasive tests) who meet the contemporary eligibility criteria for metabolic surgery will be eligible for participation. Patients meeting the inclusion and exclusion criteria and who give informed consent will be enrolled in the trial and undergo the baseline liver biopsy. 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.

The primary site of this multicenter, international, randomized controlled trial (RCT) is at the Cleveland Clinic main campus in Cleveland, Ohio, USA.

Inclusion criteria

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)

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
• Any surgery requiring general anesthesia within 1 month prior to signing the consent
• History of solid organ transplant
• Severe pulmonary disease defined as FEV1 < 50% of predicted value
• Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
• Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
• Classified as New York Heart Association Class IV
• Left ventricular ejection fraction <25% at the time of screening
• Myocardial infarction, unstable angina, stroke, heart surgery, coronary stent placement in the past 6 months
• Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis
• Presence of large hiatal hernia (>7 cm)
• Presence of Crohn's disease
• Psychiatric disorders including (but not limited to) dementia, active psychosis, severe depression requiring 3 or more medications, history of suicide attempts, active alcohol, or substance abuse within the previous 12 months that in the opinion of the investigators could disqualify the patient from metabolic surgery
• Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures
• Breastfeeding
• Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal cell cancer of the skin)
• Anemia defined as hemoglobin less than 9 g/dL
• On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)
• Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis
• Clinical judgment that life expectancy is less than 3 years
• Use of investigational therapy within 3 months prior to signing the consent
• History of pancreatic carcinoma
• Acute pancreatitis < 180 days before screening
• History or presence of chronic pancreatitis
• Presence of concerning thyroid nodule
• Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) > 6.0 mIU/L or < 0.1 mIU/L 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.
• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Evidence or history of ascites or spontaneous bacterial peritonitis that require(d) treatment

• Trace ascites identified only by an abdominal imaging without other evidence of clinically significant portal hypertension and esophageal varices is not an exclusion criterion.
• Evidence or history of hepatic encephalopathy
• Evidence or history of variceal bleeding
• Evidence or history of portosplenic vein thrombosis
• Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to the first study visit.

• Defined as more than 14 units/week for females (>1 drink per day) and more than 21 units/week for males (>2 drinks per day) on average, where one unit of alcohol is equivalent to a 12-oz beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor.
• Treatment with medications (for more than 14 consecutive days) with known effect on liver steatosis (e.g., treatment with systemic corticosteroids [oral or intravenous], methotrexate, tamoxifen, valproic acid, amiodarone, or tetracycline) in the 3 months prior to the first study visit (or historical liver biopsy).
• ALT or AST or Alkaline phosphatase >200 U/L
• Recurrent major hypoglycemia or hypoglycemic unawareness
• Inability to safely obtain a liver biopsy
• Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study
• Unable to understand the risks, benefits, and compliance requirements of study
• Lack capacity to give informed consent
• Plans to move outside the primary location of study (country) within the next 24 months
• Known or suspected allergy to semaglutide, tirzepatide, liraglutide, excipients, or related products
• Previous participation in this trial and got randomized to one of the study groups but did not proceed.
• Hospitalization due to COVID-19 within 2 months prior to screening.
• Platelet count <80,000
• International Normalized Ratio (INR) >1.7
• Child-Pugh score B or C
• MELD score ≥15
• Upper endoscopy showing gastroesophageal varices
• Upper endoscopy showing more than mild portal hypertensive gastropathy
• Liver vascular ultrasound (duplex ultrasonography) showing significant portal hypertension characterized by dilated portal vein (>13 mm), biphasic or reverse flow in the portal vein, enlarged paraumbilical veins, splenorenal collaterals, or dilated left and short gastric veins.

Note: Negative findings on upper endoscopy and liver duplex ultrasound (done within one year of the first study visit for both tests) are necessary to establish eligibility for the FLAMES.

• 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
• Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites

• Splenomegaly alone (in the absence of other radiological and laboratory findings) is not considered to be a sign of clinically significant portal hypertension and is not an exclusion criterion.
• HVPG ≥ 12 mmHg (if available historically or if measured at the time of de novo liver biopsy)
• Liver biopsy characteristics:

• 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