A Randomized Controlled Study Evaluating Bariatric Surgery as a Treatment for Severe NASH With Advanced Liver Fibrosis in Non-severe Obese Patients

Study Overview
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Brief Summary
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The aim of the study is to demonstrate the superiority of bariatric surgery on the disappearance of NASH without worsening of fibrosis in comparison to medical standard treatment in obese patients (35 kg/m² > BMI ≥ 30 kg/m²) with NASH complicated of advanced fibrosis (F3 and F4 fibrosis grade according to Brunt score).

Official Title
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Prospective Multicentric, Open Label, Randomized Clinical Trial of Superiority, With Two Arms, Comparing Bariatric Surgery to the Recommended Medical Treatment for NASH

Conditions
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Surgery, Obesity, NASH - Nonalcoholic Steatohepatitis, Cirrhosis

Intervention / Treatment
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* Other: Lifestyle therapy
* Procedure: Bariatric surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent and agree to comply to the study protocol prior to enrolment. BMI and Brunt Fibriosis score: For F3 fibrosis patients: 35>BMI≥ 30kg/m² ; Fibroscan ≥ 9kPa or FibrometreVM ≥0.526 predicting a F3 fibrosis score grade within 1 month before inclusion or F3 fibrosis score grade diagnosed by hepatic biopsy performed before inclusion. For F4 fibrosis patients: 50>BMI≥ 30kg/m² ; Fibroscan ≥ 15kPa predicting a F4 fibrosis score grade within 1 month before inclusion or F4 fibrosis score grade diagnosed by hepatic biopsy performed before inclusion. Fibroscan ≥ 9kPa or FibrometreVM ≥0.526 predicting a F3 or F4 fibrosis score grade within 1 month before inclusion Or F3 or F4 fibrosis score grade diagnosed by hepatic biopsy performed before inclusion. Patient should agree to have one liver biopsy during the screening period (before randomization, the randomization will be permitted after at least a second reading performed by pathologist of CHRU Lille to confirm the histological diagnosis of NASH with advanced fibrosis (F3-F4)) for the diagnosis purpose (if no histological biopsy within 1 month before inclusion is available) and one at the end of the treatment period for assessment of the treatment effects. For patients with cirrhosis, patients must fulfil all the following criteria: Platelets > 125 000, PT > 80 %, Albumin > 35 g/L, MELD score at inclusion < 9, CPT score < 6, No history of previous decompensation, No oesophageal varices (endoscopy), No vascular shunt, ASA score ≤ III, Alcohol consumption lower than 20g/day for women and 30g/day for men. For hypertensive patients, hypertension must be controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study). Female participating in the study must be either of non-child bearing (surgically sterilized at 6 month prior to screening or postmenopausal) or using an efficient contraception: hormonal contraception (including patch, contraceptive ring etc) intra-uterine device or other mechanical contraception Patient agrees to come to the study visits within the protocol-specified delay Exclusion Criteria: Previous history of bariatric surgery (except gastric ring removed for more than 3 years). Decompensated cirrhosis (MELD> 7 CPT score> 5, previous history of decompensation (encephalopathy, ascites, jaundice, varicose vein rupture) Hepatocellular carcinoma Platelets <125 000; TP <80%; bilirubin <20 mmol / l; albumin <35 g / L. Other liver disease: alcohol consumption exceeding 20 g / day for women and 30g / day in men, HBV, HCV, CBP, CSP, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin. Being processed Cancer (chemotherapy, radiotherapy or hormone therapy) HIV positive patients Patients who had an acute cardiovascular episode, coronary Heart Disease (Angina pectoris, myocardial infarction, revascularization procedure), stroke or TIA (Transient Ischemic Attack) within the 6 months prior to screening Recent cardiovascular events (stroke, myocardial infarcts, etc…) in the past 6 months. Severe chronic respiratory disease. Severe chronic cardiac insufficiency (grade III and IV of NYHA classification). Pregnant or breastfeeding women. Simultaneous enrollment in another clinical trial. Drug abuse within the past year. Patient with contra-indication for bariatric surgery Gastic Banding, Biliopancreatic diversion and all the new bariatric surgery techniques are forbidden because the study design allow only the laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric Bypaass. History of cancer, except: Patients considered in remission for at least 5 years after onset of treatment. Patients Treated and believed to be cured basal or squamous cell carcinoma of the skin or resected carcinoma of the cervix

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bariatric surgery<br>Two different types of bariatric surgery can be proposed: laparoscopic Roux-en-Y Gastric Bypass or a Laparoscopic sleeve gastrectomy. Decision of the surgery type will be made according to surgical expertise, habits of investigation centers and the patient's desire. All patients receive nutritional support and therapeutic education adapted to recommendations bariatric surgery care. | Procedure: Bariatric surgery<br>* Two different types of bariatric surgery can be proposed: laparoscopic Roux-en-Y Gastric Bypass or a Laparoscopic sleeve gastrectomy<br>|
| Active Comparator: Lifestyle therapy<br>The group will received the medical standard treatment defined as lifestyle therapy combining diet with increased physical activity (standard treatment, control) (figure 1, design of study). | Other: Lifestyle therapy<br>* Lifestyle habits (caloric intake and exercise) + pedometer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of disappearance of NASH without worsening of fibrosis grade | Diagnosis of NASH on the liver biopsy | at 60 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the NAS (Nafld Activity Score) score | NAS is a histological score established on the liver biopsy. The NAS ranges form 0 to 8. 8 is associated with the highest severity. | at 60 weeks after randomization | 
| Percentage of patients achieving at least a 2 point improvement in the NAS (≥2 points) without worsening of fibrosis grade | NAS established on the liver biopsy | at 60 weeks after randomization | 
| Change in the Brunt fibrosis score, | Brunt fibrosis is a histological score ranges from 0 to 4. The Brunt fibrosis score is established on the liver biopsy. It is the recommended score for the evaluation of fibrosis in NASH and NAFLD. On the scale, 0 is an absence of fibrosis, whereas 4 matches with cirrhosis. | at 60 weeks after randomization | 
| Change in the Metavir score | METAVIR fibrosis score is established on the liver biopsy. METAVIR fibrosis is a histological score ranges from 0 to 4. This score is more discriminant than the Brunt score for the severe form of fibrosis that are included in this study.On the scale, 0 is an absence of fibrosis, whereas 4 matches with cirrhosis. | at 60 weeks after randomization | 
| Change in the fibrosis area | computerized morphometry analysis of fibrosis area | at 60 weeks after randomization | 
| Change in the SF-36 quality of life score. | SF-36 quality of life score | at 60 weeks after randomization | 
| Percentage of patients with at least one of the following complications | complications: infection, thromboembolic complications, haemorrhage, rhabdomyolysis, hepatic decompensation and death | through study completion | 
| Percentage of patient achieving 5 and 10% of weight loss from randomization to end of treatment. | Weight | at 60 weeks after randomization | 
| Change in aspartate transaminase (AST) | AST is a liver enzyme, used for the biological liver test evaluation. | at 60 weeks after randomization | 
| Change in Alanine transaminase (ALT) | ALT is a liver enzyme, used for the biological liver test evaluation. | at 60 weeks after randomization | 
| Change in total bilirubin | Total bilirubin is a liver enzyme, used for the biological liver test evaluation. | at 60 weeks after randomization | 
| Change in GGT | GGT (gamma glutamyl transferase) is a liver enzyme, used for the biological liver test evaluation. . | at 60 weeks after randomization | 
| Change in ALP | Alkalin Phosphatase is a liver enzyme, used for the biological liver test evaluation. | at 60 weeks after randomization | 
| Change in INR (International Normalized Ratio) | INR represents coagulation but also liver hepatocellular function. | at 60 weeks after randomization | 
| Change in Albumin | Albumin is used a marker of nutrition and hepatocellular function | at 60 weeks after randomization | 
| Change in metabolic profile assessed by HOMA score | HOMA is a score (scale) evaluating insulin resistance. | at 60 weeks after randomization | 
| Change in Fasting glucose | fasting glucose is a marker of diabetes and insulin resistance | at 60 weeks after randomization | 
| Change in Glycated haemoglobin | glycated haemoglobin is a surrogate marker for diabetes management and outcome. | at 60 weeks after randomization | 
| Change in HDL cholesterol | HDL cholesterol is a biomarker for lipid metabolism and cardiovascular risk | at 60 weeks after randomization | 
| Change in serum triglycerides | serum triglycerides is a biomarker for lipid metabolism and cardiovascular risk | at 60 weeks after randomization | 
| Change in LDL cholesterol | LDL cholesterol is a biomarker for lipid metabolism and cardiovascular risk | at 60 weeks after randomization | 
| Change in total cholesterol. | total cholesterol is a biomarker for lipid metabolism and cardiovascular risk | at 60 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric bypass, Sleeve gastrectomy, Lifestyle therapy, NASH, Advanced fibrosis, Cirrhosis