Multicenter, Randomized, Controlled and Double-blind Study of Efficacy and Safety of Endoscopic Gastric Tubulization in Patients With Non-alcoholic Steatohepatitis (NASH-APOLLO).

Study Overview
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Brief Summary
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Nonalcoholic steatohepatitis is a growing public health problem affecting over 5% of the population. These patients are at increased risk of cardiovascular and liver-related death and have higher rates of malignancy. The currently standard of care is weight loss and physical exercise, with histological and analytical improvement in patients achieving a 5-10% reduction in body weight. However, less than 25% of the subjects achieve this goal. In obese patients , restrictive surgical treatments and gastric bypass have been successful in improving the metabolic syndrome, insulin resistance and liver histology. Currently, less invasive and less costly endoscopic techniques are being developed. These techniques also achieve a gastric restriction with similar results than bariatric surgery. One of these is the OverStitch® system (Apollo Endosurgery, Austin, TX, USA). Our aim is to evaluate the efficacy and safety of this method in the improvement of liver histology in obese patients with nonalcoholic steatohepatitis.

Official Title
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Multicenter, Randomized, Controlled and Double-blind Study of Efficacy and Safety of Endoscopic Gastric Tubulization in Patients With Non-alcoholic Steatohepatitis (NASH-APOLLO).

Conditions
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Obesity, Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Device: Endoscopic Gastric Tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA)
* Behavioral: Lifestyle modification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women aged between 18 and 75 years (inclusive) at the time of the first screening visit. They must provide signed written informed consent and agree to comply the study protocol Body mass index> 30 kg / m². 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 fibrosis of 0 to <4, according to the staging system of CRN fibrosis on NASH. NAS score ≥ 4. For patients without fibrosis or with stage 1 fibrosis, the NAS score≥5 and one of the following conditions (metabolic syndrome (definition NCEP ATP III), DM type II, HOMA-IR> 6). The liver biopsy should have been done with a 16 G trucut needle and the minimum size should be 25 mm. Exclusion Criteria: Known heart failure (Grade I to IV of the classification of the New York Heart Association). History of effective bariatric surgery in the 5 years prior to selection. 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. Liver cirrhosis. Non-cirrhotic portal hypertension. 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. 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. In addition to the above criteria, the patient must not present any of the following biological exclusion criteria: Antibodies positive for the human immunodeficiency virus. 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: 75 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: Multicenter, randomized,controlled and double-blind study with two parallel arms, placebo (normal endoscopy and lifestyle modification) or endoscopic gastric tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA) and lifestyle modification.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Diagnostic upper endoscopy plus lifestyle modification. | Behavioral: Lifestyle modification<br>* Hypocaloric diet and moderate physical exercise<br>|
| Active Comparator: Treatment<br>Endoscopic gastric tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA) plus lifestyle modification. | Device: Endoscopic Gastric Tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA)<br>* This endoscopic technique is defined as a gastric restriction by means of sutures of the entire gastric wall, 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>Behavioral: Lifestyle modification<br>* Hypocaloric diet and moderate physical exercise<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of gastric tubulization + modification in lifestyle for 72 weeks compared to standard treatment / placebo in the resolution of NASH 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. | 72 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with improvement of fibrosis according to the CRN score NASH. | to evaluate other histological changes after 72 weeks of treatment (CRN) | 72 weeks | 
| Non alcoholic fatty liver disease (NASH) activity score (NAS). | Number of patients with improvement in histological scores CRN score on NASH (NAS) | 72 weeks | 
| steatosis-activity-fibrosis index score (steatosis activity fibrosis, SAF). | Number of patients with improvement in the SAF score. | 72 weeks | 
| Cardiovascular and death events related to the liver | To evaluate the CV events in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Changes in liver enzymes | To evaluate liver enzymes in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Changes in the noninvasive markers of fibrosis and steatosis | To evaluate the noninvasive markers in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Changes in lipid parameters | To evaluate the lipid parameters in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Variation in body weight | To evaluate body weight in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Biomarkers of endothelial and macrophage dysfunction | To evaluate macrophage function in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Changes in markers of homeostasis of glucose and insulin resistance | To evaluate the glucose metabolism in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Changes in cardiovascular risk profile | To evaluate cardiovascular risk profile in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 
| Changes in quality of life (abbreviated health questionnaire SF-36). | To evaluate the following endpoints in patients treated with gastric endoscopic tubulization + lifestyle modification with respect to lifestyle modification / placebo | 72 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endoscopic gastric tubulization, Non-alcoholic steatohepatitis, NASH, Non-Alcoholic Fatty Liver Disease, Obesity