Does scarring liver fat improve after drug therapy compared to weight-reducing surgery (FLAMES)?

Brazil, Canada, Finland, India, Ireland, Italy, Kuwait, Mexico, Spain, Sweden, Switzerland, United Kingdom, United States (ICTRP)

ICTRP Trial ID
NCT06374875 (ICTRP)

Official title (approved by ethics committee)
FLAMES - Fibrosis Lessens After Metabolic Surgery A Prospective Multicenter International Randomized Controlled Trial Comparing Surgical and Medical Therapies in the Treatment of Advanced Metabolic Dysfunction-Associated Steatohepatitis (BASEC)

Academic title
A Prospective Multicenter International Randomized Controlled Trial Comparing Surgical and Medical Therapies in the Treatment of Advanced Metabolic Dysfunction Associated Steatohepatitis (ICTRP)

Public title
Fibrosis Lessens After Metabolic Surgery (ICTRP)

Disease under investigation
Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)Non-Alcoholic Fatty Liver DiseaseMetabolic Dysfunction-Associated Steatohepatitis (MASH)Liver FibrosisObesity (ICTRP)

Intervention under investigation
Procedure: Metabolic surgeryDrug: Incretin-Based Therapy (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Single (Outcomes Assessor). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria

Entry into the study would require that the patient:

1. Is a candidate for general anesthesia

2. Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022
guidelines

3. Has insurance coverage for metabolic surgery (the requirements may vary in each
country)

4. Is =18 and =75 years old at the time of signing the informed consent

5. Has a BMI =35 and =70 kg/m2 at the time of first study visit

6. FIB-4 = 1.3

7. 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

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)

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

10. Has the ability and willingness to participate in the study, provide informed
consent, and agree to any of the arms involved in the study

11. 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

12. Has a negative urine pregnancy test at the first and at the randomization visits for
women of childbearing potential.

13. 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:

1. 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

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.

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.

4. Type 1 diabetes or autoimmune diabetes

5. Known cases of human immunodeficiency virus infection

6. 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.

7. Prior complex foregut surgery including any esophageal and gastric surgeries,
anti-reflux procedures, biliary diversion, and complex trauma surgery

8. Any surgery requiring general anesthesia within 1 month prior to signing the consent

9. History of solid organ transplant

10. Severe pulmonary disease defined as FEV1 < 50% of predicted value

11. Significant cardiac or atherosclerotic disease (planned to undergo cardiac,
coronary, carotid, or peripheral artery revascularization procedures in the next 12
months)

12. Severe uncompensated cardiopulmonary disease leading to American Society of
Anesthesiologists Class IV or V

13. Classified as New York Heart Association Class IV

14. Left ventricular ejection fraction <25% at the time of screening

15. Myocardial infarction, unstable angina, stroke, heart surgery, coronary stent
placement in the past 6 months

16. Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis

17. Presence of large hiatal hernia (>7 cm)

18. Presence of Crohn's disease

19. 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

20. Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive
measures

21. Breastfeeding

22. Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal
cell cancer of the skin)

23. Anemia defined as hemoglobin less than 9 g/dL

24. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants
(DOACs)

25. Known history of clotting disorders, including pulmonary embolus and deep vein
thrombosis

26. Clinical judgment that life expectancy is less than 3 years

27. Use of investigational therapy within 3 months prior to signing the consent

28. History of pancreatic carcinoma

29. Acute pancreatitis < 180 days before screening

30. History or presence of chronic pancreatitis

31. Presence of concerning thyroid nodule

32. 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.

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

Tra (ICTRP)

not available

Primary and secondary end points
Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy. (ICTRP)

MASH resolution in the repeat liver biopsy;MASH resolution and fibrosis improvement in the repeat liver biopsy;Fibrosis progression in the repeat liver biopsy;Average Weight loss percentage;Disease-specific Quality of Life (QoL) (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Ali Aminian, MD;Chytaine Hall, hallc1@ccf.org, 216-445-3983, The Cleveland Clinic, (ICTRP)

Secondary trial IDs
24-213 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT06374875 (ICTRP)