Fibrosis Lessens After Metabolic Surgery
- Conditions
- Non-Alcoholic Fatty Liver DiseaseMetabolic Dysfunction-Associated Steatohepatitis (MASH)Liver FibrosisObesityMetabolic Dysfunction-associated Steatotic Liver Disease (MASLD)
- Interventions
- Procedure: Metabolic surgeryDrug: Incretin-Based Therapy
- Registration Number
- NCT06374875
- Lead Sponsor
- Ali Aminian
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 120
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Metabolic Surgery Metabolic surgery 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. Incretin-Based Therapy 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. 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.
- Primary Outcome Measures
Name Time Method Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy. Through study completion, 2 years 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.
- Secondary Outcome Measures
Name Time Method MASH resolution in the repeat liver biopsy Through study completion, 2 years 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
MASH resolution and fibrosis improvement in the repeat liver biopsy Through study completion, 2 years Presence of both MASH resolution and fibrosis improvement in the repeat liver biopsy
Fibrosis progression in the repeat liver biopsy Through study completion, 2 years 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
Average Weight loss percentage Through study completion, 2 years Mean percentage weight loss from baseline
Disease-specific Quality of Life (QoL) Through study completion, 2 years 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.
Trial Locations
- Locations (22)
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
University College Dublin
🇮🇪Dublin, Ireland
Clarunis Universitäres
🇨🇭Basel, Switzerland
Hôpitaux universitaires de Genève
🇨🇭Geneva, Switzerland
Instituto Nacional de Ciencias Médicas y Nutrición Salvador
🇲🇽Mexico City, Mexico
Banner Health Center
🇺🇸Phoenix, Arizona, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
The Digestive Health Institute
🇮🇳Mumbai, India
Hospital Alemão Oswaldo Cruz
🇧🇷São Paulo, Brazil
Turku University Hospital
🇫🇮Turku, Finland
Sri Aurobindo Institute of Medical Sciences
🇮🇳Indore, India
Sapienza Università di Roma
🇮🇹Roma, Italy
Università Cattolica del Sacro Cuore
🇮🇹Milan, Italy
Hospital Clínic Barcelona
🇪🇸Barcelona, Spain
Kuwait University
🇰🇼Kuwait, Kuwait
Örebro University
🇸🇪Örebro, Sweden
McGill University
🇨🇦Montréal, Canada
Linköping University
🇸🇪Linköping, Sweden
Nuffield Health Bristol Hospital
🇬🇧Bristol, United Kingdom
Queen Mary University
🇬🇧London, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom