ESG vs GLP-1RA vs ESG + GLP-1RA in Patients With Obesity, NAFLD and Advanced Fibrosis: A Randomized Controlled Trial

Study Overview
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Brief Summary
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Endoscopic bariatric and metabolic therapies (EBMT) are a non-invasive, safe alternative treatment for patients with obesity. Current FDA- approved devices include intragastric balloons (IGB) and suturing devices for endoscopic sleeve gastroplasty (ESG). These gastric interventions work by interfering with how your stomach expands to accept and process a meal, which slows down how fast your stomach empties. ESG, the procedure we are doing in this study,involves endoscopic suturing to reduce the length and width of the stomach so that you feel full faster. Semaglutide is a popular medication for weight loss, and has shown significant weight loss with a good safety profile in clinical trials. In this study, we will compare ESG, Semaglutide only, and an ESG + Semaglutide combination, on weight loss for subjects undergoing the procedure with a history of obesity, liver fibrosis and NAFLD. To better understand how these impact obesity and liver fibrosis, we will track weight loss, laboratory values, liver stiffness, and your overall liver health. The suturing device used in the ESG procedure and the semaglutide are all approved by the U.S. Food and Drug Administration (FDA) for endoscopic procedures in the upper gastrointestinal tract and medication management of obesity. This is a study that will randomize patients to 1 of 3 different treatment options: ESG only, Semaglutide only or ESG + Semaglutide. We want to see if adding the weight loss medication to the ESG procedure will increase weight loss and how it will impact liver health.

Detailed Description
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The National Institutes of Health, the World Health Organization, and numerous other scientific organizations including the America Medical Association (AMA) recognize obesity as a chronic disease requiring primary therapy. More than one-third of United States adults are obese. The increasing prevalence of obesity in the U.S. has been accompanied by an increasing prevalence in its associated comorbid conditions including hypertension, diabetes, dyslipidemia, coronary heart disease, stroke, sleep apnea, osteoarthritis, gallbladder disease, GERD, nonalcoholic fatty liver disease (NAFLD), and cancer. Obesity is associated with an increased risk of all-cause and cardiovascular mortality and accounts for about 2.5 million preventable deaths annually. The economic consequences of obesity are enormous, and projected increases may threaten the integrity of our health care system. Recent analyses estimate that 147 to 210 billion dollars are spent annually to treat obesity-attributable medical problems in the United States, accounting for about 21% of health care expenditures. Current treatment options for patients with obesity include lifestyle intervention, obesity pharmacotherapy, and bariatric surgery. The components of lifestyle intervention include diet, exercise, and behavior modification and should be considered the cornerstone of any obesity treatment. However, as a stand-alone therapy, even intensive lifestyle intervention is only modestly effective with an expected percent total body weight loss (%TBWL) < 3%. The available pharmacological approaches for the treatment of obesity increase weight loss by 3% to 9% compared with lifestyle therapy alone, but some can be associated with unfavorable side effects, significant cost, and weight loss achieved by pharmacotherapy is rarely maintained upon withdrawal of the medication. The scientific literature is clear in showing that the magnitude of weight loss is strongly associated with improvement in obesity related co-morbidities such as diabetes, blood pressure, hyperlipidemia, obstructive sleep apnea, and fatty liver disease. The odds of clinically significant improvements in obesity related co-morbidities are much higher when %TBWL exceeds 10%. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, can achieve significant and durable weight loss that exceeds the 10% TBWL threshold in the majority of patients; however, it is estimated that less than 1% of patients with severe obesity (body mass index [BMI] ≥ 40 kg/m₂) undergo surgical interventions given high costs, patient preference, access to care, and the morbidity and mortality associated with surgery. More importantly, the majority of patients with mild to moderate obesity (BMI 30-40 kg/m2) who do not qualify for bariatric surgery are left without an effective management approach to their disease, considering the modest effects seen with medications or lifestyle intervention alone and their ability to achieve >10%TBWL only in the minority of patients. Yet, according to the global disability-adjusted life-years and deaths study, patients with mild to moderate obesity are the highest contributors to the burden on disease both in terms or co-morbidities and overall mortality. Therefore, both government agencies (the Agency for Healthcare Research and Quality [AHRQ]) and national societies (American Society of Bariatric and Metabolic Surgery [ASMBS], and American Society of Gastrointestinal Endoscopy [ASGE]) now recognize that a significant management gap exists for patients with mild to moderate obesity (BMI between 30-40 kg/m2) and have defined safety and efficacy thresholds for endoscopic weight loss interventions to achieve societal recommendations. Recently the FDA has approved endoscopic bariatric therapies (EBTs) such as intragastric balloons (IGB) for the management of obesity. These endoscopic therapies can achieve >10%TBWL in the majority of patients with excellent safety and lower cost (roughly one quarter of the cost of bariatric surgery). Furthermore, they are anatomy preserving, reversible, repeatable, and are thus well positioned to fill the gap in the management of obesity. Endoscopic Sleeve Gastroplasty (ESG) is an endoscopic minimally invasive weight loss procedure where a commercially available, FDA approved, full-thickness endoscopic suturing device (Overstitch; Apollo Endosurgery, Austin, TX) is used to reduce the stomach volume by 80% through the creation of a restrictive endoscopic sleeve. This is accomplished by a series of endolumenally placed full-thickness sutures through the gastric wall, extending from the antrum to the gastroesophageal junction. We currently perform this procedure as a standard of care, primary obesity treatment at BWH. Semaglutide is an FDA approved GLP-1 receptor agonist for treatment of type 2 diabetes mellitus and is used clinically for the medical management of diabetes and obesity. Phase-3 clinical trials have demonstrated the significant weight reduction capability of Semaglutide. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated the anti-obesity potential of semaglutide. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis. Figure 1 shows the mechanism of semaglutide for management of obesity, NASH and neurodegenerative diseases.

Official Title
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Endoscopic Sleeve Gastroplasty (ESG) Versus Glucagon-like Peptide 1 Receptor Agonist (GLP-1RA) Versus ESG + GLP-1RA in Patients With Obesity, Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis: A Randomized Controlled Trial

Conditions
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Insulin Resistance, Obesity, Liver Diseases, Liver Fibrosis, Liver Fat, NAFLD, Weight Loss, Insulin Sensitivity, Insulin Sensitivity/Resistance, Metabolic Diseases, Diabetes, Diabetes Mellitus, Type 2, Diabetes Mellitus, NASH With Fibrosis, Non-Alcoholic Fatty Liver Disease, Non Alcoholic Fatty Liver, Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Device: ESG
* Drug: GLP1-RA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21-65 BMI ≥ 30 and ≤40 kg/m² Willingness to comply with the substantial lifelong dietary restrictions required by the treatment plan History of failure with non-surgical weight-loss methods Willingness to follow protocol requirements, including signed informed consent, routine follow-up schedule, completing laboratory tests, and completing diet counseling Residing within a reasonable distance from the investigator's office and able to travel to the investigator to complete all routine follow- up visits Ability to give informed consent Women of childbearing potential (i.e., not post-menopausal or surgically sterilized) must agree to use adequate birth control methods Exclusion Criteria: History of foregut or gastrointestinal (GI) surgery (except uncomplicated cholecystectomy or appendectomy) Prior gastrointestinal surgery with sequelae, i.e. obstruction, and/or adhesive peritonitis or known abdominal adhesions. Prior open or laparoscopic bariatric surgery. Prior surgery of any kind on the esophagus, stomach or any type of hiatal hernia surgery. Any inflammatory disease of the gastrointestinal tract including severe (LA Grade C or D) esophagitis, Barrett's esophagus, gastric ulceration, duodenal ulceration, cancer or specific inflammation such as Crohn's disease. Potential upper gastrointestinal bleeding conditions such as esophageal or gastric varices, congenital or acquired intestinal telangiectasis, or other congenital anomalies of the gastrointestinal tract such as atresias or stenoses. Gastrointestinal stromal tumors, history of premalignant gastric lesions (intestinal metaplasia), history of familial and nan-familial adenomatous syndromes. A gastric mass or gastric polyps > 1 cm in size. A hiatal hernia > 4cm of axial displacement of the z-line above the diaphragm or severe or intractable gastro-esophageal reflux symptoms. A structural abnormality in the esophagus or pharynx such as a stricture or diverticulum that could impede passage of the endoscope. Achalasia or any other severe esophageal motility disorder Severe coagulopathy. Insulin-dependent diabetes (either Type 1 or Type 2) or a significant likelihood of requiring insulin treatment in the following 12 months or a HgbA1C≥9. Subjects with any serious health condition unrelated to their weight that would increase the risk of endoscopy Chronic abdominal pain Motility disorders of the GI tract such as gross esophageal motility disorders, gastroparesis or intractable constipation Hepatic insufficiency or cirrhosis Use of an intragastric device prior to this study due to the increased thickness of the stomach wall preventing effective suturing. Active, untreated psychological issues preventing participation in a life-style modification program Patients unwilling to participate in an established medically-supervised diet and behavior modification program, with routine medical follow-up. Patients receiving daily prescribed treatment with high dose aspirin (> 80mg daily), anti-inflammatory agents, anticoagulants or other gastric irritants. Patients who are unable or unwilling to take prescribed proton pump inhibitor medication Patients who are pregnant or breast-feeding. Subjects with Severe cardiopulmonary disease or other serious organic disease which might include known history of coronary artery disease, Myocardial infarction within the past 6 months, poorly-controlled hypertension, required use of NSAIDs Subjects taking medications on specified hourly intervals that may be affected by changes to gastric emptying, such as anti-seizure or anti-arrhythmic medications Subjects who are taking corticosteroids, immunosuppressants, and narcotics Symptomatic congestive heart failure, cardiac arrhythmia or unstable coronary artery disease. Pre-existing respiratory disease such as moderate or severe chronic obstructive pulmonary disease (COPD) requiring steroids, pneumonia or cancer. Diagnosis of autoimmune connective tissue disorder (e.g. lupus, erythematous, scleroderma) or immunocompromised. Specific diagnosed genetic disorder such as Prader Willi syndrome. Eating disorders including night eating syndrome (NES), bulimia, binge eating disorder, or compulsive overeating Known history of endocrine disorders affecting weight such as uncontrolled hypothyroidism.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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: Factorial Assignment
Interventional Model Description: This study is a randomized, controlled, open-label clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ESG + GLP-1RA treatment<br>Endoscopic sleeve gastroplasty suturing procedure with a prescription regimen of semaglutide (2.4 mg injection per week) for 12 months. | Device: ESG<br>* Endoscopic sleeve gastroplasty - reduce the size of the stomach using an endoscopic plicating device<br>* Other names: Endoscopic Suturing;Drug: GLP1-RA<br>* Prescription for semaglutide for weight loss for 12 months.<br>* Other names: Semaglutide;|
| Active Comparator: ESG Only<br>Endoscopic sleeve gastroplasty suturing procedure. | Device: ESG<br>* Endoscopic sleeve gastroplasty - reduce the size of the stomach using an endoscopic plicating device<br>* Other names: Endoscopic Suturing;|
| Active Comparator: GLP-1RA Only<br>Semaglutide prescription (2.4mg injection per week) regimen for 12 months. | Drug: GLP1-RA<br>* Prescription for semaglutide for weight loss for 12 months.<br>* Other names: Semaglutide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Liver Fibrosis measurement at 12 months compared to baseline | Comparison of Endoscopic ultrasound (EUS)-guided liver biopsy results to assess for change in liver fibrosis from baseline in the ESG + GLP-1RA group compared to ESG only and GLP-1RA only | Baseline, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Liver stiffness at 12 months compared to baseline | Compare the magnetic resonance elastography (MRE) results of the liver from baseline in the ESG + GLP-1RA group compared to ESG only and GLP-1RA only. | Baseline, 12 months | 
| Change in liver fibrosis at 12 months compared to baseline | Fibroscan score from baseline in the ESG + GLP-1RA group compared to ESG only and GLP-1RA only | Baseline, 12 months | 
| Change in liver scarring at 12 months compared to baseline | Fibrosis-4 (FIB-4) Score from baseline in the ESG + GLP-1RA group compared to ESG only and GLP-1RA only. | Baseline, 12 months | 
| Change in %TBWL compared to baseline for ESG + GLP-1RA compared to ESG | Compare weight measurements from baseline for ESG + GLP-1RA compared to ESG only | Baseline, 1, 3, 6, 9 and 12 months | 
| Change in %TBWL compared to baseline for ESG + GLP-1RA compared to GLP-1RA | Compare weight measurements from baseline for ESG + GLP-1RA compared to GLP-1RA only | Baseline, 1, 3, 6, 9 and 12 months | 
| Change in quality of life compared to baseline | Compare changes in quality of life assessed using standard validated questionnaires (IWQOL-lite, PHQ-9 and SF-36) | Baseline, 1, 3, 6, 9 and 12 months | 
| Change in eating behaviors compared to baseline | Compare changes in eating behaviors evaluated using the Three Factor Eating Questionnaire (TFEQ) | Baseline, 3 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut Hormones, Endoscopic Bariatric Therapies (EBT), Intragastric Balloon (IGB), Endoscopic Suturing, endoscopic sleeve gastroplasty (ESG), GLP-1RA, Glucagon-like peptide 1 receptor agonist, Weight Management, Endoscopic bariatric and metabolic therapies (EBMT)