Fibrosis Lessens After Metabolic Surgery

Obesity Clinical Trial

— FLAMES  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06374875
• Other study ID #: 24-213
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 1, 2024
• Est. completion date: December 31, 2029

Study information

• Verified date: April 2024
• Source: The Cleveland Clinic
• Contact: Chytaine Hall
• Phone: 216-445-3983
• Email: hallc1[@]ccf.org
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 120
• Est. completion date: December 31, 2029
• Est. primary completion date: May 31, 2029
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion 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)

a. In patients with a historical noninvasive tests or liver biopsy, weight change of no more than 5% is allowed from 90 days prior to the historical tests until 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.

Exclusion Criteria:

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

a. Reversed procedures such as gastric band or intragastric balloon that have been removed at least 6 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. 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

Related Conditions & MeSH terms

• Fatty Liver
• Fibrosis
• Liver Cirrhosis
• Liver Diseases
• Liver Fibrosis
• Non-Alcoholic Fatty Liver Disease
• Obesity

Intervention

Procedure:
• Metabolic surgery
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

Drug:
• Incretin-Based Therapy
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.

Locations

Country	Name	City	State
Brazil	Hospital Alemão Oswaldo Cruz	São Paulo
Canada	McGill University	Montréal
Finland	Turku University Hospital	Turku
India	Sri Aurobindo Institute of Medical Sciences	Indore
India	The Digestive Health Institute	Mumbai
Ireland	University College Dublin	Dublin
Italy	Università Cattolica del Sacro Cuore	Milan
Italy	Sapienza Università di Roma	Roma
Kuwait	Kuwait University	Kuwait
Mexico	Instituto Nacional de Ciencias Médicas y Nutrición Salvador	Mexico City
Spain	Hospital Clínic Barcelona	Barcelona
Sweden	Linköping University	Linköping
Sweden	Örebro University	Örebro
Switzerland	Clarunis Universitäres	Basel
Switzerland	Hôpitaux universitaires de Genève	Geneva
United Kingdom	Nuffield Health Bristol Hospital	Bristol
United Kingdom	King's College Hospital	London
United Kingdom	Queen Mary University	London
United States	Cleveland Clinic	Cleveland	Ohio
United States	Indiana University	Indianapolis	Indiana
United States	Banner Health Center	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Ali Aminian

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	MASLD-related histopathologic end points	Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification, regardless of changes in MASH severity; Progression to cirrhosis (F4) in repeat liver biopsy among patients who did not have F4 in the baseline liver biopsy; Mean and change from baseline in NAFLD Activity Score; Reduction in NAFLD Activity Score by at least 1, 2, or 3 points; Histopathological changes in severity of steatosis, inflammation, hepatocyte ballooning, and fibrosis; Histopathological changes in modified Ishak fibrosis score; Histopathological changes in features of regression (Beijing classification, P-I-R fibrosis quality)	Through study completion, 2 years
Other	MASLD-related laboratory end points	Mean and change from baseline in ALT, AST, Alkaline phosphatase, bilirubin, platelet count, eGFR, and FIB-4	Through study completion, 2 years
Other	MASLD-related liver scan end points	Change in liver stiffness in elastography (based on the same device that was used at baseline)	Through study completion, 2 years
Other	MASLD-related clinical end points	Development of adverse clinical outcomes including development of ascites or hydrothorax (requiring treatment including diuretics), hepatic encephalopathy (requiring treatment or hospitalization), bleeding esophageal varices, liver-related mortality, and all-cause mortality as a composite and individual end points	Through study completion, 2 years
Other	Achieved Weight-loss proportions	Proportion of participants achieving = 5%, = 10%, = 15%, = 20%, = 25%, = 30%, = 35% weight loss from baseline (yes/no) in each two groups	Through study completion, 2 years
Other	Weight change (kg)	Absolute change in weight (kg)	Through study completion, 2 years
Other	BMI change (kg/m^2)	Absolute change in BMI (kg/m^2)	Through study completion, 2 years
Other	Excess weight loss, %	Calculated by dividing the difference between initial BMI and final BMI by the difference between initial BMI and a target BMI of 25	Through study completion, 2 years
Other	Change in waist circumference, cm	Change in circumferential measurement above the level of the iliac crests	Through study completion, 2 years
Other	Systolic blood pressure trends, mmHg	Mean and change in systolic blood pressure, mmHg	Through study completion, 2 years
Other	Mean and change from baseline in lipid panel, mg/dl	Mean and change from baseline in total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides	Through study completion, 2 years
Other	Changes in glucose hemostasis markers	Mean and change from baseline in blood glucose, HbA1c, and fasting homoeostasis model of assessment of insulin resistance (HOMA-IR) in patients with T2DM	Through study completion, 2 years
Other	Percentage of patients with T2DM meeting predefined HbA1c targets	HbA1c <6.5% (without diabetes medications); HbA1c <7% (irrespective of taking diabetes medications or not)	Through study completion, 2 years
Other	Changes in inflammatory markers, CRP mg/L	Mean and change from baseline in C-Reactive Protein (CRP)	Through study completion, 2 years
Other	Change in cardiovascular and diabetes medications	Change in number of cardiovascular and diabetes medications prescribed	Through study completion, 2 years
Other	SF-Bari Score	Swiss-Finnish Bariatric Metabolic Outcome Score (SF-BARI Score) which combines four areas of clinical interest in obesity treatment (weight loss, outcomes of four major obesity-related comorbidities, complications, and QoL) in one score. The SF-BARI Score range is from -100 to 200 and the SF-BARI Score QOL is from -130 to 230. The total score ranges from suboptimal (scores below 35) to excellent (scores equal or greater than 135). Research coordinator completes the survey with the patient.	Through study completion, 2 years
Other	Quality of life end points	Change from baseline in score of The 36-Item Short Form Health Survey (SF-36) (physical and mental components). Each item is given a score ranging from 0-100. Lower scores indicating poor outcomes. Final score is an average of all the items that were answered. Unanswered questions are not included in the final average. Research coordinator completes the survey with the patient.	Through study completion, 2 years
Other	Safety end points	Complications specifically related to MASH disease, as well as complications of liver biopsy, metabolic surgery, liraglutide, semaglutide, tirzepatide, and other medications will be recorded and evaluated.	Through study completion, 2 years
Primary	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.	Through study completion, 2 years
Secondary	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	Through study completion, 2 years
Secondary	MASH resolution and fibrosis improvement in the repeat liver biopsy	Presence of both MASH resolution and fibrosis improvement in the repeat liver biopsy	Through study completion, 2 years
Secondary	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	Through study completion, 2 years
Secondary	Average Weight loss percentage	Mean percentage weight loss from baseline	Through study completion, 2 years
Secondary	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.	Through study completion, 2 years