Clinical trial NCT06138821: Effect of Endoscopic Sleeve Gastroplasty in Patients With Obesity and MASH: A Randomized Controlled Trial
Official title: Effect of Endoscopic Sleeve Gastroplasty on Patients With Obesity and Concomitant Metabolic Dysfunction-Associated Steatohepatitis (MASH): A Multicenter, Open-label, Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Obesity
Liver Diseases
Liver Fibrosis
Liver Fat
Metabolic Dysfunction-Associated Steatotic Liver Disease
Metabolic Dysfunction-Associated Steatohepatitis
MASLD
MASH
Weight Loss
Insulin Resistance
Insulin Sensitivity
Insulin Sensitivity/Resistance
Metabolic Disease
Diabetes
Diabetes Mellitus, Type 2
NASH With Fibrosis
Non-Alcoholic Fatty Liver Disease
Non Alcoholic Fatty Liver
Non-alcoholic Steatohepatitis
Keywords: Gut Hormones
Endoscopic Bariatric and Metabolic Therapy (EBMT)
Intragastric Balloon (IGB)
Endoscopic Suturing
Endoscopic Sleeve Gastroplasty (ESG)
Weight Management
Endoscopic Gastric Remodeling (EGR)
Endoscopic Bariatric Therapy (EBT)
Fatty Liver
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Non-Alcoholic Fatty Liver Disease (NAFLD)
Non-Alcoholic Steatohepatitis (NASH)
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2023-11-18
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a randomized, controlled, open-label clinical trial.
Primary purpose: TREATMENT

Brief summary: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally. While weight loss through lifestyle modification is the standard treatment, most patients regain weight limiting ultimate improvement in liver disease. On the other end of the spectrum, bariatric surgery has shown promise in the treatment of MASLD/metabolic dysfunction-associated steatohepatitis (MASH) due to its efficacy in inducing weight loss. Nevertheless, its adoption has been hindered by the perceived invasiveness of surgery.

Over the past decade, endoscopic sleeve gastroplasty (ESG) has gained recognition as a promising minimally-invasive approach to weight loss. The procedure involves utilizing a Food and Drug Administration (FDA)-authorized endoscopic suturing device to reduce the gastric volume by 70%. Studies reveal that ESG is associated with approximately 18.2% weight loss at one year after the procedure, with sustained results for at least 10 years. Nevertheless, the effect of ESG on MASH remains unknown.

In this study, the investigators will compare ESG + lifestyle modification versus lifestyle modification alone in treating histologic MASH. The study will randomize patients to one of two different treatment options: ESG + lifestyle modification or lifestyle modification alone.

Detailed description: 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. Almost half of United States (U.S.) adults have obesity. 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, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). The economic consequences of MASH are enormous, with the lifetime cost of care for all patients with MASH projected to be approximately $222 billion as of 2017.

Current treatment options for patients with MASLD/MASH are limited to lifestyle modification and the more recent Food and Drug Administration (FDA)-approved medication called resmetirom. Nevertheless, less than 10% of patients who undergo lifestyle modification experience at least 10% total weight loss (TWL), the threshold required for fibrosis regression. On the other end of the spectrum, bariatric surgery has shown promise in the treatment of MASLD/metabolic dysfunction-associated steatohepatitis (MASH) due to its efficacy in inducing weight loss. Nevertheless, its adoption has been hindered by the perceived invasiveness of surgery.

Over the past decades, endoscopic bariatric and metabolic therapies (EBMTs) have been developed to fill the treatment gap for obesity and MASLD/MASH. Specifically, compared to lifestyle modification, EBMTs are associated with greater weight loss with a higher proportion of patients reaching the 10% TWL threshold. Additionally, given its non-surgical, minimally-invasive nature, the safety profile for EBMTs appears more favorable compared to bariatric surgery. To date, there are two EBMT devices and/or procedures that are approved or cleared by the FDA. These include intragastric balloons (IGBs) and endoscopic sleeve gastroplasty (ESG).

The ESG procedure is an endoscopic minimally-invasive weight loss procedure where a commercially available, FDA-approved, full-thickness endoscopic suturing device (Overstitch; Boston Scientific, Marlborough, MA) is used to reduce the stomach volume by 70% through the creation of a restrictive endoscopic sleeve. This is accomplished by a series of endoluminally placed full-thickness sutures through the gastric wall, extending from the distal gastric body to the proximal gastric body. The investigators currently perform this procedure as a standard of care at Brigham and Women's Hospital (BWH). Our previous studies have demonstrated that ESG not only leads to significant weight loss, but also improves non-invasive tests (NITs) of liver steatosis and fibrosis, as well as MASH histologic features in patients with obesity and concomitant MASH. Nevertheless, it remains unclear if ESG is superior to lifestyle modification alone.

Eligibility criteria: Inclusion Criteria:

1. 18 years or older
2. Obesity with a body mass index of 30-50 kg/m2
3. A diagnosis of MASH with stage 1 (F1), 2 (F2), or 3 (F3) fibrosis (on a scale of 0 \[no fibrosis\] to 4 \[cirrhosis\]). MASH is defined as the nonalcoholic fatty liver disease activity score (NAS) of 4 or higher, with a score of 1 or higher for each subcomponent: steatosis, hepatocyte ballooning and lobular inflammation). Grading and staging of biopsies for the purposes of enrollment are done by a liver pathologist at the site of enrollment.

Exclusion Criteria:

1. cirrhosis
2. excessive alcohol consumption (\>20 g per day for women; \>30 g per day for men)
3. active smoking
4. active malignancy
5. being on an anticoagulant or anti-platelet medication
6. being on a glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 (SGLT2) inhibitor of any dose
7. being initiated on an anti-obesity medication within 6 months prior to study enrollment or 12 months after study enrollment
8. history of bariatric surgery or bariatric endoscopy
9. changes in weight by greater than 5% within 6 months of study enrollment
10. hemoglobin A1c (HbA1c) ≥10%

Primary outcomes:
measure: MASH resolution without worsening of liver fibrosis at 12 months
timeFrame: Baseline, 12 months
Secondary outcomes:
measure: An improvement of liver fibrosis by at least one stage without worsening of MASH at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver stiffness on MRE at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver stiffness on VCTE at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver fibrosis using NFS at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver fibrosis using ELF score at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver fibrosis using FIB-4 at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver fat content using MRI-PDFF at 12 months
timeFrame: Baseline, 12 months
measure: Change in liver fat content using VCTE CAP score at 12 months
timeFrame: Baseline, 12 months
measure: Percent total weight loss (%TWL) at 12 months
timeFrame: Baseline, 1, 3, 6 and 12 months
measure: Change in quality of life at 12 months
timeFrame: Baseline, 6 and 12 months
measure: Change in eating behaviors at 12 months
timeFrame: Baseline, 6 and 12 months
measure: Change in insulin resistance at 12 months
timeFrame: Baseline, 12 months.
measure: Safety parameters post-procedure
timeFrame: Procedure day, 1, 3, 6, 9 and 12 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Pichamol Jirapinyo, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010 Jan 20;303(3):235-41. doi: 10.1001/jama.2009.2014. Epub 2010 Jan 13.
citation: Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013 Jan 2;309(1):71-82. doi: 10.1001/jama.2012.113905.
citation: Adams KF, Schatzkin A, Harris TB, Kipnis V, Mouw T, Ballard-Barbash R, Hollenbeck A, Leitzmann MF. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med. 2006 Aug 24;355(8):763-78. doi: 10.1056/NEJMoa055643. Epub 2006 Aug 22.
citation: Prospective Studies Collaboration; Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009 Mar 28;373(9669):1083-96. doi: 10.1016/S0140-6736(09)60318-4. Epub 2009 Mar 18.
citation: Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood). 2009 Sep-Oct;28(5):w822-31. doi: 10.1377/hlthaff.28.5.w822. Epub 2009 Jul 27.
citation: Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012 Jan;31(1):219-30. doi: 10.1016/j.jhealeco.2011.10.003. Epub 2011 Oct 20.
citation: Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2985-3023. doi: 10.1016/j.jacc.2013.11.004. Epub 2013 Nov 12. No abstract available.
citation: Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, Smith West D, Milas NC, Mattfeldt-Beman M, Belden L, Bragg C, Millstone M, Raczynski J, Brewer A, Singh B, Cohen J; Trials for the Hypertension Prevention Research Group. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med. 2001 Jan 2;134(1):1-11. doi: 10.7326/0003-4819-134-1-200101020-00007.
citation: Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, Bantle J, Pownall HJ, Johnson KC, Safford MM, Kitabchi AE, Pi-Sunyer FX, Wing RR, Bertoni AG; Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012 Dec 19;308(23):2489-96. doi: 10.1001/jama.2012.67929.
citation: Look AHEAD Research Group; Pi-Sunyer X, Blackburn G, Brancati FL, Bray GA, Bright R, Clark JM, Curtis JM, Espeland MA, Foreyt JP, Graves K, Haffner SM, Harrison B, Hill JO, Horton ES, Jakicic J, Jeffery RW, Johnson KC, Kahn S, Kelley DE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montgomery B, Nathan DM, Patricio J, Peters A, Redmon JB, Reeves RS, Ryan DH, Safford M, Van Dorsten B, Wadden TA, Wagenknecht L, Wesche-Thobaben J, Wing RR, Yanovski SZ. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 2007 Jun;30(6):1374-83. doi: 10.2337/dc07-0048. Epub 2007 Mar 15.
citation: Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014 Jan 1;311(1):74-86. doi: 10.1001/jama.2013.281361.
citation: Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, Hill JO, Brancati FL, Peters A, Wagenknecht L; Look AHEAD Research Group. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011 Jul;34(7):1481-6. doi: 10.2337/dc10-2415. Epub 2011 May 18.
citation: Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg. 2013 Apr;23(4):427-36. doi: 10.1007/s11695-012-0864-0.
citation: GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12.
citation: ASGE Bariatric Endoscopy Task Force; Sullivan S, Kumar N, Edmundowicz SA, Abu Dayyeh BK, Jonnalagadda SS, Larsen M, Thompson CC. ASGE position statement on endoscopic bariatric therapies in clinical practice. Gastrointest Endosc. 2015 Nov;82(5):767-72. doi: 10.1016/j.gie.2015.06.038. Epub 2015 Aug 15. No abstract available.
citation: Mahapatra MK, Karuppasamy M, Sahoo BM. Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review. Pharm Res. 2022 Jun;39(6):1233-1248. doi: 10.1007/s11095-022-03302-1. Epub 2022 Jun 1.
citation: Abu Dayyeh BK, Rajan E, Gostout CJ. Endoscopic sleeve gastroplasty: a potential endoscopic alternative to surgical sleeve gastrectomy for treatment of obesity. Gastrointest Endosc. 2013 Sep;78(3):530-5. doi: 10.1016/j.gie.2013.04.197. Epub 2013 May 24.
citation: Sharaiha RZ, Kedia P, Kumta N, DeFilippis EM, Gaidhane M, Shukla A, Aronne LJ, Kahaleh M. Initial experience with endoscopic sleeve gastroplasty: technical success and reproducibility in the bariatric population. Endoscopy. 2015 Feb;47(2):164-6. doi: 10.1055/s-0034-1390773. Epub 2014 Nov 7.
citation: Lopez-Nava G, Galvao MP, da Bautista-Castano I, Jimenez A, De Grado T, Fernandez-Corbelle JP. Endoscopic sleeve gastroplasty for the treatment of obesity. Endoscopy. 2015 May;47(5):449-52. doi: 10.1055/s-0034-1390766. Epub 2014 Nov 7.
citation: Abu Dayyeh BK, Acosta A, Camilleri M, Mundi MS, Rajan E, Topazian MD, Gostout CJ. Endoscopic Sleeve Gastroplasty Alters Gastric Physiology and Induces Loss of Body Weight in Obese Individuals. Clin Gastroenterol Hepatol. 2017 Jan;15(1):37-43.e1. doi: 10.1016/j.cgh.2015.12.030. Epub 2015 Dec 31.
citation: ASGE/ASMBS Task Force on Endoscopic Bariatric Therapy; Ginsberg GG, Chand B, Cote GA, Dallal RM, Edmundowicz SA, Nguyen NT, Pryor A, Thompson CC. A pathway to endoscopic bariatric therapies. Gastrointest Endosc. 2011 Nov;74(5):943-53. doi: 10.1016/j.gie.2011.08.053. No abstract available.
citation: Mechanick JI, Youdim A, Jones DB, Timothy Garvey W, Hurley DL, Molly McMahon M, Heinberg LJ, Kushner R, Adams TD, Shikora S, Dixon JB, Brethauer S. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013 Mar-Apr;9(2):159-91. doi: 10.1016/j.soard.2012.12.010. Epub 2013 Jan 19.
citation: Abu Dayyeh BK, Bazerbachi F, Vargas EJ, Sharaiha RZ, Thompson CC, Thaemert BC, Teixeira AF, Chapman CG, Kumbhari V, Ujiki MB, Ahrens J, Day C; MERIT Study Group; Galvao Neto M, Zundel N, Wilson EB. Endoscopic sleeve gastroplasty for treatment of class 1 and 2 obesity (MERIT): a prospective, multicentre, randomised trial. Lancet. 2022 Aug 6;400(10350):441-451. doi: 10.1016/S0140-6736(22)01280-6. Epub 2022 Jul 28.
citation: Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015 Aug;149(2):367-78.e5; quiz e14-5. doi: 10.1053/j.gastro.2015.04.005. Epub 2015 Apr 10.
citation: Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, Moussa SE, Neff GW, Rinella ME, Anstee QM, Abdelmalek MF, Younossi Z, Baum SJ, Francque S, Charlton MR, Newsome PN, Lanthier N, Schiefke I, Mangia A, Pericas JM, Patil R, Sanyal AJ, Noureddin M, Bansal MB, Alkhouri N, Castera L, Rudraraju M, Ratziu V; MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024 Feb 8;390(6):497-509. doi: 10.1056/NEJMoa2309000.
citation: Jirapinyo P, Zucker SD, Thompson CC. Regression of Hepatic Fibrosis After Endoscopic Gastric Plication in Nonalcoholic Fatty Liver Disease. Am J Gastroenterol. 2023 Jun 1;118(6):983-990. doi: 10.14309/ajg.0000000000002087. Epub 2022 Dec 23.
citation: Jirapinyo P, Thompson CC, Garcia-Tsao G, Zucker SD, Ryou M. The effect of endoscopic gastric plication on portosystemic pressure gradient in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease. Endoscopy. 2024 Jan;56(1):56-62. doi: 10.1055/a-2146-8857. Epub 2023 Aug 2.
citation: Jirapinyo P, Hadefi A, Thompson CC, Patai AV, Pannala R, Goelder SK, Kushnir V, Barthet M, Apovian CM, Boskoski I, Chapman CG, Davidson P, Donatelli G, Kumbhari V, Hayee B, Esker J, Hucl T, Pryor AD, Maselli R, Schulman AR, Pattou F, Zelber-Sagi S, Bain PA, Durieux V, Triantafyllou K, Thosani N, Huberty V, Sullivan S. American Society for Gastrointestinal Endoscopy-European Society of Gastrointestinal Endoscopy guideline on primary endoscopic bariatric and metabolic therapies for adults with obesity. Gastrointest Endosc. 2024 Jun;99(6):867-885.e64. doi: 10.1016/j.gie.2023.12.004. Epub 2024 Apr 19.