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

Sponsor

Instituto de Investigación Marqués de Valdecilla (Other)

Overall Status

Recruiting

CT.gov ID

NCT04060368

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Non-alcoholic Steatohepatitis (NASH)	Procedure: Endoscopic Sleeve Gastroplasty (ESG) with OverStitch® system + Lifestyle modifications Procedure: Laparoscopic Sleeve Gastrectomy (LSG) + Lifestyle modifications	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Experimental: Endoscopic Sleeve Gastroplasty with OverStitch® system + Lifestyle modifications Comparator: Laparoscopic Sleeve Gastrectomy + Lifestyle modificationsExperimental: Endoscopic Sleeve Gastroplasty with OverStitch® system + Lifestyle modifications Comparator: Laparoscopic Sleeve Gastrectomy + Lifestyle modifications

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Jun 1, 2020

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ESG Stitch® system + Lifestyle modifications 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 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).
Active Comparator: LSG + Lifestyle modifications 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 Minimally invasive surgical technique defined as a gastric restriction by means of an excision approximately 80% of the stomach along the greater curvature.

Arm

Intervention/Treatment

Experimental: ESG Stitch® system + Lifestyle modifications

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

Active Comparator: LSG + Lifestyle modifications

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

Minimally invasive surgical technique defined as a gastric restriction by means of an excision approximately 80% of the stomach along the greater curvature.

Outcome Measures

Primary Outcome Measures

Proportion of subjects undergoing ESG relative to LSG achieving resolution of NASH without worsening of fibrosis [Measurement at 96 weeks]
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.
Proportion of subjects undergoing ESG relative to LSG with cardiovascular and liver-related death events [Measurement at 96 weeks]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.