Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)Phase 4FLAMESNCT06374875
Fibrosis Lessens After Metabolic Surgery
A Phase 4 study testing Metabolic surgery and Incretin-Based Therapy in people with Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) and Non-Alcoholic Fatty Liver Disease, run by The Cleveland Clinic at 22 sites in 13 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Non-Alcoholic Fatty Liver Disease, Metabolic Dysfunction-Associated Steatohepatitis (MASH)
- What is being tested?
- Metabolic surgery and Incretin-Based Therapy
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 22 sitesin 13 countries
- Study dates
- 11 Jul 2024to 31 Dec 2029
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
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- 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)
- 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
Who cannot join
None listed.
Trial locations and contacts
22 sites in 13 countries. Contact the study team or a site near you to ask about taking part.
22 sites in 13 countries
United States4 sites, 4 recruiting
- Recruiting
Cleveland Clinic
Cleveland, Ohio, 44195
Ali Aminian, MD, aminiaa@ccf.org
- Not yet recruiting
Indiana University
Indianapolis, Indiana, 46202
Dimitrios Stefanidis, MD, PhD, dstefanidis@iuhealth.org
- Not yet recruiting
Banner Health Center
Phoenix, Arizona, 85006
Farah Husain, MD, Farah.husain@bannerhealth.com
- Not yet recruiting
Mayo Clinic
Rochester, Minnesota, 55905
Omar Ghanem, MD, ghanem.omar@mayo.edu
United Kingdom3 sites, 3 recruiting
- Not yet recruiting
Nuffield Health Bristol Hospital
Bristol
Dimitri Pournaras, PhD, dpournaras@doctors.org.uk
- Not yet recruiting
King's College Hospital
London
Francesco Rubino, MD, francesco.rubino@kcl.ac.uk
- Not yet recruiting
Queen Mary University
London
William Alazawi, MB BChir PhD, w.alazawi@qmul.ac.uk
India2 sites, 2 recruiting
- Not yet recruiting
Sri Aurobindo Institute of Medical Sciences
Indore
Mohit Bhandari, MS, DMAS, drmohitbhandari@gmail.com
- Not yet recruiting
The Digestive Health Institute
Mumbai
Muffazal Lakdawala, MBBS, M.S., drmuffi@thedigestive.in
Italy2 sites, 2 recruiting
- Not yet recruiting
Università Cattolica del Sacro Cuore
Milan
Geltrude Mingrone, M.D. PhD, geltrude.mingrone@unicatt.it
- Not yet recruiting
Sapienza Università di Roma
Roma
Giovanni Casella, MD, giovanni.casella@uniroma1.it
Sweden2 sites, 2 recruiting
- Not yet recruiting
Linköping University
Linköping
Torsten Olbers, MD, PhD, torsten.olbers@liu.se
- Not yet recruiting
Örebro University
Örebro
Erik Stenberg, MD, PhD, erik.stenberg@regionorebrolan.se
Switzerland2 sites, 2 recruiting
- Not yet recruiting
Clarunis Universitäres
Basel
Ralph Peterli, Dr. med, ralph.peterli@clarunis.ch
- Not yet recruiting
Hôpitaux universitaires de Genève
Geneva
Minoa Jung, PD Dr. med., minoa.jung@hcuge.ch
Brazil1 site, 1 recruiting
- Recruiting
Hospital Alemão Oswaldo Cruz
São Paulo
Ricardo Cohen, MD, ricardo.cohen@haoc.com.br
Canada1 site, 1 recruiting
- Not yet recruiting
McGill University
Montreal
Amin Andalib, MDCM, MSc, amin.andalib@mcgill.ca
Finland1 site, 1 recruiting
- Not yet recruiting
Turku University Hospital
Turku
Paulina Salminen, MD, PhD, paulina.salminen@tyks.fi
Ireland1 site, 1 recruiting
- Not yet recruiting
University College Dublin
Dublin
Helen Heneghan, MB BCh BAO, PhD, helen.heneghan@ucd.ie
Kuwait1 site, 1 recruiting
- Not yet recruiting
Kuwait University
Kuwait City
Mohammad Jamal, MBChB (HONS) MEd, mjamal110@gmail.com
Mexico1 site, 1 recruiting
- Not yet recruiting
Instituto Nacional de Ciencias Médicas y Nutrición Salvador
Mexico City
Mauricio Sierra, MD
Spain1 site, 1 recruiting
- Not yet recruiting
Hospital Clínic Barcelona
Barcelona
Josep Vidal, MD, PhD, jovidal@clinic.cat
About this study
Official title: A Prospective Multicenter International Randomized Controlled Trial Comparing Surgical and Medical Therapies in the Treatment of Advanced Metabolic Dysfunction Associated Steatohepatitis
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.
Read the detailed description
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.
- Conditions
- Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Non-Alcoholic Fatty Liver Disease, Metabolic Dysfunction-Associated Steatohepatitis (MASH), Liver Fibrosis, Obesity
- Being tested
- Metabolic surgery, Incretin-Based Therapy
- Medical subject headings
- Non-alcoholic Fatty Liver Disease, Liver Cirrhosis, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metabolic surgeryProcedure or surgery
Also called Bariatric surgery, Roux-en-Y Gastric Bypass (RYGB), Sleeve Gastrectomy (SG)
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
Incretin-Based TherapyDrug
Also called Glucagon-like Peptide-1 Receptor Agonist
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Incretin-Based Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Through study completion, 2 years
Secondary outcomes (5)
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
Measured: Through study completion, 2 years
MASH resolution and fibrosis improvement in the repeat liver biopsy
Presence of both MASH resolution and fibrosis improvement in the repeat liver biopsy
Measured: Through study completion, 2 years
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
Measured: Through study completion, 2 years
Average Weight loss percentage
Mean percentage weight loss from baseline
Measured: Through study completion, 2 years
Disease-specific Quality of Life (QoL)
Change from baseline in score of a disease-specific QoL instrument: Chronic Liver Disease Questionnaire (CLDQ) for NASH (CLDQ-NASH). This instrument collects data on 36 items grouped into 6 domains: abdominal symptoms, activity/energy, emotional health, fatigue, systemic symptoms, and worry. In all domains, greater scores (between 1-7) reflect better health, and the average of the domain scores yields the total CLDQ-NASH score. Research coordinator completes the survey with the patient.
Measured: Through study completion, 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2024
- Study start11 Jul 2024
- Primary completion31 May 2029 (estimated)
- Study completion31 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)Studies of the same condition, open and under way.
- More trials run by The Cleveland ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Cleveland Clinic
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ali Aminian, The Cleveland Clinic
- Investigators
- Ali Aminian, MD, Principal investigator, The Cleveland Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06374875
- Sponsor's protocol ID
- 24-213
- Acronym
- FLAMES
- Status last verified
- Jul 2026
- First submitted
- 16 Apr 2024
- Last updated
- 31 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes