RECRUITING

Fibrosis Lessens After Metabolic Surgery

Conditions

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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

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

Quick Facts

Study Start:2024-07-11

Study Completion:2029-12-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06374875

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 70 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:Yes

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Is a candidate for general anesthesia 2. Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines 3. Is ≥18 and ≤70 years old 4. Has a BMI ≥35 and ≤60 kg/m\^2 at the time of first study visit 5. FIB-4 ≥ 1.3 6. 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 7. 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%. 8. Self-reported stable weight in 3 months before the first study visit (no weight change \>5% within 3 months prior to the first study visit) 9. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study. 10. 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. 11. Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential. 12. Women of childbearing age must agree to use reliable method of contraception for 2 years.	1. Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic): 1. Hepatitis B as detected by presence of hepatitis B surface antigen (HBsAg) 2. 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) 3. Autoimmune liver disease as diagnosed by antibodies or compatible liver histology 4. 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) 5. Primary sclerosing cholangitis 6. Wilson's disease as diagnosed by low ceruloplasmin or compatible liver histology 7. Alpha-1-antitrypsin deficiency as diagnosed by alpha1-antitrypsin level or liver histology 8. Hemochromatosis as diagnosed by HFE mutations (C282Y, H63D), ferritin and transferrin saturation levels, or presence of 3+ or 4+ stainable iron on liver biopsy 9. Drug-induced liver disease diagnosed by medical history 10. Known bile duct obstruction 11. Suspected or proven liver cancer 2. Treatment with semaglutide, tirzepatide, or liraglutide for obesity or for T2DM \<90 days before the first study visit 3. Treatment with vitamin E (at doses ≥800 IU/day), pioglitazone, obeticholic acid, or resmetirom \<90 days before the first study visit 4. Type 1 diabetes or autoimmune diabetes 5. Known cases of human immunodeficiency virus infection 6. Prior bariatric and metabolic surgery of any kind 7. Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery 8. Thoracic, abdominal, pelvic, or obstetric-gynecologic surgery within 6 months prior to signing the consent 9. Any other surgery requiring general anesthesia within 6 weeks prior to signing the consent 10. History of solid organ transplant 11. Severe pulmonary disease defined as FEV1 \< 50% of predicted value 12. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months) 13. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V 14. Classified as New York Heart Association Class IV 15. Left ventricular ejection fraction \<25% at the time of screening 16. Myocardial infarction, unstable angina, stroke, transient ischemic attack, heart surgery, coronary stent placement in the past 6 months 17. Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis 18. Presence of large hiatal hernia (\>7 cm) 19. Presence of Crohn's disease 20. 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 21. Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures 22. Breastfeeding 23. Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal cell cancer of the skin) 24. Anemia defined as hemoglobin less than 9 g/dL 25. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs) 26. Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis 27. Clinical judgment that life expectancy is less than 3 years 28. Use of investigational therapy within 3 months prior to signing the consent 29. History of pancreatic carcinoma 30. Acute pancreatitis \< 180 days before screening 31. History or presence of chronic pancreatitis 32. History of thyroid cancer 33. Presence of concerning thyroid nodule 34. Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) \> 6.0 mIU/L or \< 0.4 mIU/L before the first study visit 35. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 36. Evidence or history of ascites or spontaneous bacterial peritonitis 37. Evidence or history of hepatic encephalopathy 38. Evidence or history of variceal bleeding 39. Evidence or history of portosplenic vein thrombosis 40. 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. 41. 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). 42. ALT or AST or Alkaline phosphatase \>200 U/L 43. Recurrent major hypoglycemia or hypoglycemic unawareness 44. Inability to safely obtain a liver biopsy 45. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study 46. Unable to understand the risks, benefits, and compliance requirements of study 47. Lack capacity to give informed consent 48. Plans to move outside the primary location of study (country) within the next 24 months 49. Known or suspected allergy to semaglutide, tirzepatide, liraglutide, excipients, or related products 50. Previous participation in this trial and got randomized to one of the study groups but did not proceed. 51. Hospitalization due to COVID-19 within 2 months prior to screening. 52. Platelet count \<100,000 53. International Normalized Ratio (INR) \>1.7 54. Child-Pugh score B or C 55. MELD score ≥12 56. Upper endoscopy showing gastroesophageal varices 57. Upper endoscopy showing more than mild portal hypertensive gastropathy 58. 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. 59. Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites 60. HVPG ≥ 10 mmHg (if available historically or if measured at the time of de novo liver biopsy

Inclusion Criteria

Exclusion Criteria

1. Is a candidate for general anesthesia
2. Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines
3. Is ≥18 and ≤70 years old
4. Has a BMI ≥35 and ≤60 kg/m\^2 at the time of first study visit
5. FIB-4 ≥ 1.3
6. 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
7. 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%.
8. Self-reported stable weight in 3 months before the first study visit (no weight change \>5% within 3 months prior to the first study visit)
9. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study.
10. 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.
11. Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential.
12. Women of childbearing age must agree to use reliable method of contraception for 2 years.

1. Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic):
1. Hepatitis B as detected by presence of hepatitis B surface antigen (HBsAg)
2. 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)
3. Autoimmune liver disease as diagnosed by antibodies or compatible liver histology
4. 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)
5. Primary sclerosing cholangitis
6. Wilson's disease as diagnosed by low ceruloplasmin or compatible liver histology
7. Alpha-1-antitrypsin deficiency as diagnosed by alpha1-antitrypsin level or liver histology
8. Hemochromatosis as diagnosed by HFE mutations (C282Y, H63D), ferritin and transferrin saturation levels, or presence of 3+ or 4+ stainable iron on liver biopsy
9. Drug-induced liver disease diagnosed by medical history
10. Known bile duct obstruction
11. Suspected or proven liver cancer
2. Treatment with semaglutide, tirzepatide, or liraglutide for obesity or for T2DM \<90 days before the first study visit
3. Treatment with vitamin E (at doses ≥800 IU/day), pioglitazone, obeticholic acid, or resmetirom \<90 days before the first study visit
4. Type 1 diabetes or autoimmune diabetes
5. Known cases of human immunodeficiency virus infection
6. Prior bariatric and metabolic surgery of any kind
7. Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery
8. Thoracic, abdominal, pelvic, or obstetric-gynecologic surgery within 6 months prior to signing the consent
9. Any other surgery requiring general anesthesia within 6 weeks prior to signing the consent
10. History of solid organ transplant
11. Severe pulmonary disease defined as FEV1 \< 50% of predicted value
12. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
13. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
14. Classified as New York Heart Association Class IV
15. Left ventricular ejection fraction \<25% at the time of screening
16. Myocardial infarction, unstable angina, stroke, transient ischemic attack, heart surgery, coronary stent placement in the past 6 months
17. Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis
18. Presence of large hiatal hernia (\>7 cm)
19. Presence of Crohn's disease
20. 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
21. Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures
22. Breastfeeding
23. Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal cell cancer of the skin)
24. Anemia defined as hemoglobin less than 9 g/dL
25. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)
26. Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis
27. Clinical judgment that life expectancy is less than 3 years
28. Use of investigational therapy within 3 months prior to signing the consent
29. History of pancreatic carcinoma
30. Acute pancreatitis \< 180 days before screening
31. History or presence of chronic pancreatitis
32. History of thyroid cancer
33. Presence of concerning thyroid nodule
34. Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) \> 6.0 mIU/L or \< 0.4 mIU/L before the first study visit
35. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
36. Evidence or history of ascites or spontaneous bacterial peritonitis
37. Evidence or history of hepatic encephalopathy
38. Evidence or history of variceal bleeding
39. Evidence or history of portosplenic vein thrombosis
40. 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.
41. 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).
42. ALT or AST or Alkaline phosphatase \>200 U/L
43. Recurrent major hypoglycemia or hypoglycemic unawareness
44. Inability to safely obtain a liver biopsy
45. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study
46. Unable to understand the risks, benefits, and compliance requirements of study
47. Lack capacity to give informed consent
48. Plans to move outside the primary location of study (country) within the next 24 months
49. Known or suspected allergy to semaglutide, tirzepatide, liraglutide, excipients, or related products
50. Previous participation in this trial and got randomized to one of the study groups but did not proceed.
51. Hospitalization due to COVID-19 within 2 months prior to screening.
52. Platelet count \<100,000
53. International Normalized Ratio (INR) \>1.7
54. Child-Pugh score B or C
55. MELD score ≥12
56. Upper endoscopy showing gastroesophageal varices
57. Upper endoscopy showing more than mild portal hypertensive gastropathy
58. 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.
59. Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites
60. HVPG ≥ 10 mmHg (if available historically or if measured at the time of de novo liver biopsy

Contacts and Locations

Study Contact

Chytaine Hall

CONTACT

216-445-3983

hallc1@ccf.org

Principal Investigator

Ali Aminian, MD

PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Study Locations (Sites)

Banner Health Center

Phoenix, Arizona, 85006

United States

Indiana University

Indianapolis, Indiana, 46202

United States

Mayo Clinic

Rochester, Minnesota, 55905

United States

Cleveland Clinic

Cleveland, Ohio, 44195

United States

Collaborators and Investigators

Sponsor: Ali Aminian

Ali Aminian, MD, PRINCIPAL_INVESTIGATOR, The Cleveland Clinic

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2024-07-11

Study Completion Date2029-12-31

Study Record Updates

Study Start Date2024-07-11

Study Completion Date2029-12-31

Terms related to this study

Additional Relevant MeSH Terms

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