A Prospective Multicenter International Randomized Controlled Trial Comparing Surgical and Medical Therapies in the Treatment of Advanced Metabolic Dysfunction Associated Steatohepatitis
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 22
- 主要终点
- Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Patients and investigators will not be blinded to treatment assignment. The treatment assignment will remain unknown until the patient is randomized after meeting all eligibility requirements.
Pathologists who report the liver biopsies (to assess the primary end point of study) are blinded to treatment assignment
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Entry into the study would require that the patient:
- •Is a candidate for general anesthesia
- •Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines
- •Has insurance coverage for metabolic surgery (the requirements may vary in each country)
- •Is ≥18 and ≤75 years old at the time of signing the informed consent
- •Has a BMI ≥35 and ≤70 kg/m2 at the time of first study visit
- •FIB-4 ≥ 1.3
- •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
- •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%.
- •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
- •Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study
- •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
- •Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential.
- •Women of childbearing age must agree to use reliable method of contraception for 2 years
排除标准
- •Patients who meet the following criteria will be excluded from the study:
- •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
- •Weight change >10% within 6 months prior to the first study visit or prior to the historical liver biopsy
- •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.
- •Type 1 diabetes or autoimmune diabetes
- •Known cases of human immunodeficiency virus infection
- •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.
- •Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery
- •Any surgery requiring general anesthesia within 1 month prior to signing the consent
- •History of solid organ transplant
- •Severe pulmonary disease defined as FEV1 < 50% of predicted value
- •Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
- •Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
- •Classified as New York Heart Association Class IV
- •Left ventricular ejection fraction <25% at the time of screening
- •Myocardial infarction, unstable angina, stroke, heart surgery, coronary stent placement in the past 6 months
- •Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis
- •Presence of large hiatal hernia (>7 cm)
- •Presence of Crohn's disease
- •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
- •Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures
- •Breastfeeding
- •Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal cell cancer of the skin)
- •Anemia defined as hemoglobin less than 9 g/dL
- •On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)
- •Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis
- •Clinical judgment that life expectancy is less than 3 years
- •Use of investigational therapy within 3 months prior to signing the consent
- •History of pancreatic carcinoma
- •Acute pancreatitis < 180 days before screening
- •History or presence of chronic pancreatitis
- •Presence of concerning thyroid nodule
- •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.
- •A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- •Evidence or history of ascites or spontaneous bacterial peritonitis that require(d) treatment
- 另有 39 项未显示
研究组 & 干预措施
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.
干预措施: Metabolic surgery (Procedure)
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.
干预措施: Incretin-Based Therapy (Drug)
结局指标
主要结局
Improvement of at least 1 fibrosis stage of the Kleiner fibrosis classification and no worsening of MASH in the repeat liver biopsy.
时间窗: 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.
次要结局
- MASH resolution in the repeat liver biopsy(Through study completion, 2 years)
- MASH resolution and fibrosis improvement in the repeat liver biopsy(Through study completion, 2 years)
- Fibrosis progression in the repeat liver biopsy(Through study completion, 2 years)
- Average Weight loss percentage(Through study completion, 2 years)
- Disease-specific Quality of Life (QoL)(Through study completion, 2 years)
研究者
Ali Aminian
Director of Bariatric and Metabolic Institute
The Cleveland Clinic