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

Not Applicable

• Conditions: Obesity; Non-Alcoholic Fatty Liver Disease
• Interventions: Behavioral: Lifestyle modification; Device: Endoscopic Gastric Tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA)

• Registration Number: NCT03426111
• Lead Sponsor: Puerta de Hierro University Hospital

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-01-09
• Study First Submitted QC: 2018-02-01
• Study First Posted: 2018-02-08
• Study Start: 2018-04-18
• Status Verified: 2018-12
• Last Update Submitted: 2018-12-10
• Last Update Posted: 2018-12-12
• Primary Completion: 2020-12
• Study Completion: 2020-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Men or women aged between 18 and 75 years (inclusive) at the time of the first screening visit.
2. They must provide signed written informed consent and agree to comply the study protocol
3. Body mass index> 30 kg / m².
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 fibrosis of 0 to <4, according to the staging system of CRN fibrosis on NASH.
5. NAS score ≥ 4.
6. 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).
7. The liver biopsy should have been done with a 16 G trucut needle and the minimum size should be 25 mm.

Exclusion Criteria

1. Known heart failure (Grade I to IV of the classification of the New York Heart Association).

2. History of effective bariatric surgery in the 5 years prior to selection.

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. Liver cirrhosis.

6. Non-cirrhotic portal hypertension.

7. 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.

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.

    In addition to the above criteria, the patient must not present any of the following biological exclusion criteria:

16. Antibodies positive for the human immunodeficiency virus.

17. Aspartate aminotransferase (AST) and / or ALT> 10 x upper limit of normal (ULN).

18. Total bilirubin> 25 μmol / l (1.5 mg / dl).

19. Standardized international index> 1.4.

20. Platelet count <100 000 / mm3.

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

22. 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Lifestyle modification	Diagnostic upper endoscopy plus lifestyle modification.
Treatment	Endoscopic Gastric Tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA)	Endoscopic gastric tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA) plus lifestyle modification.
Treatment	Lifestyle modification	Endoscopic gastric tubulization with OverStitch® system (Apollo Endosurgery, Austin, TX, USA) plus lifestyle modification.

Primary Outcome Measures

Name	Time	Method
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.	72 weeks	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.

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Jose Luis Calleja; 🇪🇸 Majadahonda, Madrid, Spain