Efficacy and Safety of Endoscopic Sleeve Gastroplasty Versus Laparoscopic Sleeve Gastrectomy in Obese Subjects With NASH

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the effect of ESG with OverStitch® system (Apollo Endosurgery, Austin, TX, USA) compared to LSG on 1) histological improvement in NASH; 2) all-cause mortality and liver-related outcomes In obese subjects with non-alcoholic steatohepatitis (NASH). Condition or disease: Non-alcoholic steatohepatitis (NASH) with or without fibrosis Intervention/treatment: ESG with OverStitch® system vs LSG

Official Title
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STudy to Evaluate the Efficacy and Safety of Endoscopic Sleeve Gastroplasty (ESG) Versus LAparoscopic Sleeve Gastrectomy (LSG) in Obese Subjects With Non-Alcoholic SteatoHepatitis (NASH)

Conditions
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Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Procedure: Endoscopic Sleeve Gastroplasty (ESG) with OverStitch® system + Lifestyle modifications
* Procedure: Laparoscopic Sleeve Gastrectomy (LSG) + Lifestyle modifications


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged between 18 and 60 years (inclusive) at first screening visit. Must provide signed written informed consent and agree to comply with the study protocol. BMI between 35 and 45 kg/m2 with or without metabolic risk factors (type 2 diabetes, arterial hypertension, dyslipidaemia), and BMI between 30 and 34,9 kg/m2 with type 2 diabetes. Histological confirmation of steatohepatitis in a diagnostic liver biopsy (biopsy obtained in the 6 months prior to randomization or during the selection period) with at least a score of 1 in each component of the NAS score (steatosis with a score of 0 to 3, degeneration by ballooning with a score of 0 to 2 and lobular inflammation with a score of 0 to 3) and: NAS score ≥ 4 fibrosis < 4 according to the staging system of CRN fibrosis on NASH For patients with fibrosis ≤ 1, must be associated at least one of the following conditions: metabolic syndrome (NCEP ATP III definition), type 2 diabetes, HOMA-IR >6 Absence of other well documented causes of chronic liver disease (alcoholic liver disease, viral hepatitis, cholestasis, autoimmune hepatitis, Wilson's disease, hemochromatosis, alpha 1 antitrypsin deficiency) Patients agree to have 1 liver biopsy after 96 weeks after intervention Exclusion Criteria: Known heart failure (Grade I to IV of the classification of the New York Heart Association). History of efficient bariatric surgery within 10 years prior to Screening. Patients with a history of clinically significant acute cardiac event in the 6 months prior to selection, such as: acute cardiovascular event, cerebrovascular accident, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization procedures). Weight loss of more than 5% in the 6 months prior to randomization. Recent or current background of significant consumption of alcoholic beverages (<5 years). In the case of men, significant consumption is usually defined as more than 30 g of pure alcohol per day. In the case of women, it is usually defined as more than 20 g of pure alcohol per day. Liver cirrhosis. Non-cirrhotic portal hypertension. Esophagogastric varices. Hepatocellular carcinoma Portal thrombosis. Pregnancy. Refusal to give informed consent. Any medical condition that could reduce life expectancy to less than 2 years, including known cancers. Signs of any other unstable or clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric disease without treatment. Instability or mental incompetence, so that the validity of the informed consent or the ability to comply with the study are uncertain. Antibodies positive for the human immunodeficiency virus. Descompensated liver disease with the following hematologic and biochemical criteria: Aspartate aminotransferase (AST) and / or ALT> 10 x upper limit of normal (ULN) Total bilirubin> 25 μmol / l (1.5 mg / dl) Standardized international index> 1.4 Platelet count <100 000 / mm3 Serum creatinine levels> 135 μmol / l (> 1.53 mg / dl) in men and> 110 μmol / l (> 1.24 mg / dl) in women. Significant renal disease, including nephritic syndrome, chronic kidney disease (patients with markers of hepatic injury or estimated glomerular filtration rate [eGFR] of less than 60 ml / min / 1.73 m2). If an abnormal value is obtained at the first screening visit, the eGFR measurement may be repeated before randomization within the following time frame: minimum 4 weeks after the initial test and maximum 2 weeks before the expected randomization. An abnormal repeated eGFR (less than 60 ml / min / 1.73 m2) leads to exclusion from the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Interventional Model Description: Experimental: Endoscopic Sleeve Gastroplasty with OverStitch® system + Lifestyle modifications Comparator: Laparoscopic Sleeve Gastrectomy + Lifestyle modifications
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ESG Stitch® system + Lifestyle modifications<br>Endoscopic technique defined as a gastric restriction by means of continuous sutures of the entire gastric wall of the antrum and body, transmurally, in order to simulate a gastric sleeve, in the same way as sleeve gastrectomy surgery. Gastroplasty is performed using an endoscopic suture system (OverStitch, Apollo Endosurgery Inc., Austin, Texas, USA) inserted into a dual-channel endoscope (GIF-2T160, Olympus Medical Systems Corp., Tokyo, Japan). | Procedure: Endoscopic Sleeve Gastroplasty (ESG) with OverStitch® system + Lifestyle modifications<br>* Endoscopic technique defined as a gastric restriction by means of continuous sutures of the entire gastric wall of the antrum and body, transmurally, in order to simulate a gastric sleeve, in the same way as sleeve gastrectomy surgery. Gastroplasty is performed using an endoscopic suture system (OverStitch, Apollo Endosurgery Inc., Austin, Texas, USA) inserted into a dual-channel endoscope (GIF-2T160, Olympus Medical Systems Corp., Tokyo, Japan).<br>|
| Active Comparator: LSG + Lifestyle modifications<br>Minimally invasive surgical technique defined as a gastric restriction by means of an excision approximately 80% of the stomach along the greater curvature. | Procedure: Laparoscopic Sleeve Gastrectomy (LSG) + Lifestyle modifications<br>* Minimally invasive surgical technique defined as a gastric restriction by means of an excision approximately 80% of the stomach along the greater curvature.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects undergoing ESG relative to LSG achieving resolution of NASH without worsening of fibrosis | To evaluate the effect of ESG compared to LSG on liver histology in obese subjects with NASH with or without fibrosis by assessing the following endpoint: The proportion of subjects undergoing ESG relative to LSG achieving NASH resolution without worsening of fibrosis. NASH resolution is defined as the disappearance of ballooning and the disappearance or persistence of minimal lobular inflammation (grade 0 or 1) The worsening of fibrosis is defined as the progression of at least one stage. | Measurement at 96 weeks | 
| Proportion of subjects undergoing ESG relative to LSG with cardiovascular and liver-related death events | To evaluate the effect of ESG compared to LSG on liver histology in obese subjects with NASH with fibrosis by assessing the following endpoint: The proportion of subjects undergoing ESG relative to LSG achieving improvement of liver fibrosis of at least one stage. | Measurement at 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects undergoing ESG relative to LSG achieving improvement in liver histology according to the NASH-CRN scoring | Percentage of patients with at least 1 point improvement | Measurement at 96 weeks | 
| Changes in the liver enzymes | ALT, AST, GGT, AP (U/L) | Measurement at 96 weeks | 
| Changes in lipid parameter | Cholesterol, LDL, HDL, Triglycerides (mg/dL) | Measurement at 96 weeks | 
| Changes in noninvasive markers of fibrosis and steatosis | Fatty Liver Index (FLI) (<30; 30-60; >60) | Measurement at 96 weeks | 
| Changes in noninvasive markers of fibrosis and steatosis | Hepatic steatosis index (HSI) (<30; 30-36; >36) | Measurement at 96 weeks | 
| Changes in noninvasive markers of fibrosis and steatosis | NAFLD fibrosis score (NFS) (<-1.455; -1.455-0.676; >0.676) | Measurement at 96 weeks | 
| Changes in noninvasive markers of fibrosis and steatosis | AST to Plateler ratio index (APRI) (<1, >1) | Measurement at 96 weeks | 
| Changes in noninvasive markers of fibrosis and steatosis | Fibrosis-4 (FIB-4) (<1.30; 1.30-2.67; >2.67) | Measurement at 96 weeks | 
| Changes in noninvasive markers of fibrosis and steatosis | Hepamet fibrosis score (HFS) (<0.12; 0.12-0.47; >0.47) | Measurement at 96 weeks | 
| Changes in body weight | body weight | Measurement at 96 weeks | 
| Changes in inflammatory markers | Ferritin in ng/mL | Measurement at 96 weeks | 
| Changes in inflammatory markers | C-rective protein (CRP) in mg/dL | Measurement at 96 weeks | 
| Changes in inflammatory markers | High sensitivity C-reactive protein (hs-CRP) in mg/L | Measurement at 96 weeks | 
| Changes in inflammatory markers | Interleukin 6 (IL-6) in pg/mL | Measurement at 96 weeks | 
| Changes in inflammatory markers | Interleukin 1 beta (IL-1b) in pg/mL | Measurement at 96 weeks | 
| Changes in inflammatory markers | Tumor necrosis factor alpha (TNFa) in pg/mL | Measurement at 96 weeks | 
| Changes in serum expression of incretins | serum expression of incretins | Measurement at 96 weeks | 
| Changes in mineral metabolism parameters. | Parathormone (PTH) (pg/mL), 25(OH)D (ng/mL), PINP, b-CTX (ng/mL) | Measurement at 96 weeks | 
| Changes in gut microbiota | Analysis using 16S rRNA sequencing from stool samples | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Glucose in mg/dL | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Hemoglobin A1c (HbA1c) in % | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Homeostatic model assessment for insulin resistance (HOMA-IR) (not unit) | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Adponectin in ug/mL | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Retinol binding protein 4 (RBP-4) in ug/mL | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Monocyte chemoattractant protein-1 (MCP-1) in ug/mL | Measurement at 96 weeks | 
| Changes in glucose homeostasis markers and insulin resistance | Plaminogen activator inhibitor-1 (PAI-1) in ug/mL | Measurement at 96 weeks | 
| Incidence of adverse events | Safety and tolerability | Measurement at 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, Obesity, Endoscopic Sleeve Gastroplasty, Laparoscopic Sleeve Gastrectomy