Clinical trial NCT06374875: Fibrosis Lessens After Metabolic Surgery
Official title: A Prospective Multicenter International Randomized Controlled Trial Comparing Surgical and Medical Therapies in the Treatment of Advanced Metabolic Dysfunction Associated Steatohepatitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)
Non-Alcoholic Fatty Liver Disease
Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Liver Fibrosis
Obesity
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
First posted: 2024-04-19
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

    • Trace ascites identified only by an abdominal imaging without other evidence of clinically significant portal hypertension and esophageal varices is not an exclusion criterion.
35. Evidence or history of hepatic encephalopathy
36. Evidence or history of variceal bleeding
37. Evidence or history of portosplenic vein thrombosis
38. 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.
39. 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).
40. ALT or AST or Alkaline phosphatase \>200 U/L
41. Recurrent major hypoglycemia or hypoglycemic unawareness
42. Inability to safely obtain a liver biopsy
43. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study
44. Unable to understand the risks, benefits, and compliance requirements of study
45. Lack capacity to give informed consent
46. Plans to move outside the primary location of study (country) within the next 24 months
47. Known or suspected allergy to semaglutide, tirzepatide, liraglutide, excipients, or related products
48. Previous participation in this trial and got randomized to one of the study groups but did not proceed.
49. Hospitalization due to COVID-19 within 2 months prior to screening.
50. Platelet count \<80,000
51. International Normalized Ratio (INR) \>1.7
52. Child-Pugh score B or C
53. MELD score ≥15
54. Upper endoscopy showing gastroesophageal varices
55. Upper endoscopy showing more than mild portal hypertensive gastropathy
56. 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
57. 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.
58. HVPG ≥ 12 mmHg (if available historically or if measured at the time of de novo liver biopsy)
59. 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

Primary outcomes:
measure: Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy.
timeFrame: Through study completion, 2 years
Secondary outcomes:
measure: MASH resolution in the repeat liver biopsy
timeFrame: Through study completion, 2 years
measure: MASH resolution and fibrosis improvement in the repeat liver biopsy
timeFrame: Through study completion, 2 years
measure: Fibrosis progression in the repeat liver biopsy
timeFrame: Through study completion, 2 years
measure: Average Weight loss percentage
timeFrame: Through study completion, 2 years
measure: Disease-specific Quality of Life (QoL)
timeFrame: Through study completion, 2 years
Other outcomes:
measure: MASLD-related histopathologic end points
timeFrame: Through study completion, 2 years
measure: MASLD-related laboratory end points
timeFrame: Through study completion, 2 years
measure: MASLD-related liver scan end points
timeFrame: Through study completion, 2 years
measure: MASLD-related clinical end points
timeFrame: Through study completion, 2 years
measure: Achieved Weight-loss proportions
timeFrame: Through study completion, 2 years
measure: Weight change (kg)
timeFrame: Through study completion, 2 years
measure: BMI change (kg/m^2)
timeFrame: Through study completion, 2 years
measure: Excess weight loss, %
timeFrame: Through study completion, 2 years
measure: Change in waist circumference, cm
timeFrame: Through study completion, 2 years
measure: Systolic blood pressure trends, mmHg
timeFrame: Through study completion, 2 years
measure: Mean and change from baseline in lipid panel, mg/dl
timeFrame: Through study completion, 2 years
measure: Changes in glucose hemostasis markers
timeFrame: Through study completion, 2 years
measure: Percentage of patients with T2DM meeting predefined HbA1c targets
timeFrame: Through study completion, 2 years
measure: Changes in inflammatory markers, CRP mg/L
timeFrame: Through study completion, 2 years
measure: Change in cardiovascular and diabetes medications
timeFrame: Through study completion, 2 years
measure: SF-Bari Score
timeFrame: Through study completion, 2 years
measure: Quality of life end points
timeFrame: Through study completion, 2 years
measure: Safety end points
timeFrame: Through study completion, 2 years
Locations:
city: Phoenix
country: United States
facility: Banner Health Center
state: Arizona
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
city: Montréal
country: Canada
facility: McGill University
city: Turku
country: Finland
facility: Turku University Hospital
city: Indore
country: India
facility: Sri Aurobindo Institute of Medical Sciences
city: Mumbai
country: India
facility: The Digestive Health Institute
city: Dublin
country: Ireland
facility: University College Dublin
city: Milan
country: Italy
facility: Università Cattolica del Sacro Cuore
city: Roma
country: Italy
facility: Sapienza Università di Roma
city: Kuwait
country: Kuwait
facility: Kuwait University
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición Salvador
city: Barcelona
country: Spain
facility: Hospital Clínic Barcelona
city: Linköping
country: Sweden
facility: Linköping University
city: Örebro
country: Sweden
facility: Örebro University
city: Basel
country: Switzerland
facility: Clarunis Universitäres
city: Geneva
country: Switzerland
facility: Hôpitaux universitaires de Genève
city: Bristol
country: United Kingdom
facility: Nuffield Health Bristol Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Queen Mary University
Study officials:
affiliation: The Cleveland Clinic
name: Ali Aminian, MD
role: PRINCIPAL_INVESTIGATOR
References: