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

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)

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

Study Overview

• Status: Recruiting
• Conditions: Non-alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Procedure: Endoscopic Sleeve Gastroplasty (ESG) with OverStitch® system + Lifestyle modifications; Procedure: Laparoscopic Sleeve Gastrectomy (LSG) + Lifestyle modifications

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Javier Crespo, PROF; Phone Number: +34942204089; Email: javier.crespo@scsalud.es
• Study Contact Backup: Name: Paula Iruzubieta, MD, PhD; Phone Number: +34942204089; Email: p.iruzubieta@gmail.com

Study Locations

• Spain
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Recruiting
      • Hospitl Universitario Marqués de Valdecilla
      • Contact: Paula Iruzubieta, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects aged between 18 and 60 years (inclusive) at first screening visit.
2. Must provide signed written informed consent and agree to comply with the study protocol.
3. 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.

4. 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
5. 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
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)
7. Patients agree to have 1 liver biopsy after 96 weeks after intervention

Exclusion Criteria:

1. Known heart failure (Grade I to IV of the classification of the New York Heart Association).
2. History of efficient bariatric surgery within 10 years prior to Screening.
3. 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).
4. Weight loss of more than 5% in the 6 months prior to randomization.
5. 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.
6. Liver cirrhosis.
7. Non-cirrhotic portal hypertension.
8. Esophagogastric varices.
9. Hepatocellular carcinoma
10. Portal thrombosis.
11. Pregnancy.
12. Refusal to give informed consent.
13. Any medical condition that could reduce life expectancy to less than 2 years, including known cancers.
14. Signs of any other unstable or clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric disease without treatment.
15. Instability or mental incompetence, so that the validity of the informed consent or the ability to comply with the study are uncertain.
16. Antibodies positive for the human immunodeficiency virus.

17. 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
18. Serum creatinine levels> 135 μmol / l (> 1.53 mg / dl) in men and> 110 μmol / l (> 1.24 mg / dl) in women.
19. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Instituto de Investigación Marqués de Valdecilla

Publications and helpful links

General Publications

• Cuadrado A, Orive A, Garcia-Suarez C, Dominguez A, Fernandez-Escalante JC, Crespo J, Pons-Romero F. Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. Obes Surg. 2005 Mar;15(3):442-6. doi: 10.1381/0960892053576596.
• Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54.e1-9; quiz e39-40. doi: 10.1016/j.cgh.2014.04.014. Epub 2014 Apr 24.
• Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, Ratziu V; LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013 Sep;59(3):550-6. doi: 10.1016/j.jhep.2013.04.027. Epub 2013 May 9.
• Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. doi: 10.1111/j.1365-2036.2011.04724.x. Epub 2011 May 30.
• Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. 2006 Oct;45(4):600-6. doi: 10.1016/j.jhep.2006.06.013. Epub 2006 Jul 25.
• Boza C, Riquelme A, Ibanez L, Duarte I, Norero E, Viviani P, Soza A, Fernandez JI, Raddatz A, Guzman S, Arrese M. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass. Obes Surg. 2005 Sep;15(8):1148-53. doi: 10.1381/0960892055002347.
• Lavin-Alconero L, Fernandez-Lanas T, Iruzubieta-Coz P, Arias-Loste MT, Rodriguez-Duque JC, Rivas C, Cagigal ML, Montalban C, Useros AL, Alvarez-Cancelo A, Garcia-Saiz M, Crespo-Garcia J. Efficacy and safety of endoscopic sleeve gastroplasty versus laparoscopic sleeve gastrectomy in obese subjects with Non-Alcoholic SteatoHepatitis (NASH): study protocol for a randomized controlled trial (TESLA-NASH study). Trials. 2021 Oct 30;22(1):756. doi: 10.1186/s13063-021-05695-7.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2020
• Primary Completion (ANTICIPATED): June 1, 2022
• Study Completion (ANTICIPATED): June 1, 2023

Study Registration Dates

• First Submitted: July 18, 2019
• First Submitted That Met QC Criteria: August 14, 2019
• First Posted (ACTUAL): August 19, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 30, 2020
• Last Update Submitted That Met QC Criteria: September 28, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Obesity; NASH; Laparoscopic Sleeve Gastrectomy; Endoscopic Sleeve Gastroplasty
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: TESLA-NASH

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No