Effect of DMR in the Treatment of NASH

NASH - Nonalcoholic Steatohepatitis Clinical Trial

— DMR_NASH_001  

Official title:

Evaluation of Duodenal Mucosal Resurfacing (DMR) for the Treatment of Non Alcoholic Steatohepatitis (NASH), a Proof of Concept Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03536650
• Other study ID #: P2017/302
• Status: Completed
• Phase: N/A
• Start date: November 8, 2017
• Est. completion date: December 31, 2020

Study information

• Verified date: February 2021
• Source: Erasme University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Non-alcoholic fatty liver disease (NAFLD) is a frequent disease affecting up to 25% of the USA population, 2-44% in Europe and up to 42,6-69,5% in patients with type 2 diabetes. It is a disease that could progress from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic cirrhosis and hepatocarcinoma. NASH is part of continuum of metabolic syndrome and constitutes a serious public health concern manifesting by premature cardiovascular disease, end stage diabetes complication and will likely become the first cause of end stage liver disease. Insuline resistance is the hallmark of NASH. Some recent studies both in animals and humans have demonstrated abnormal hypertrophy of the duodenal mucosa, changes in enteroendocrine cell density and number, endocrine hyperplasia, and alterations in gut hormone signaling highlighting the role of the upper intestine gut in glucose homeostasis and thus insulin sensitizing. Given these physiological and pathophysiological features, abrasion of duodenal mucosa was assessed both in animals and humans. The investigators reported an improvement in both glucose homeostasis and transaminases levels suggesting possibly an improvement of NASH. Until now, lifestyle medication is the only recognized efficient treatment for fatty liver disease. Unfortunately, only a minority of patients achieve a significant weight loss and lifestyle modifications. The investigators aim to study the duodenal mucosal resurfacing procedure in patients with NASH biopsy proven in a proof of concept study allowing to assess this technique as a potential treatment to NASH.

Description:

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a frequent disease affecting up to 25% of the USA population, 2-44% in Europe and up to 42,6-69,5% in patients with type 2 diabetes. It is a disease that could progress from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic cirrhosis and hepatocarcinoma. NASH is part of continuum of a metabolic syndrome and constitutes a serious public health concern, manifesting by premature cardiovascular disease, end stage diabetes complication and will likely become the first cause of end stage liver disease.

Insulin resistance is the hallmark of NASH. Some recent studies both in animals and humans have demonstrated abnormal hypertrophy of the duodenal mucosa, changes in enteroendocrine cell density and number, endocrine hyperplasia, and alterations in gut hormone signaling highlighting the role of the upper intestine gut in glucose homeostasis and thus insulin sensitizing.

Given these physiological and pathophysiological features, abrasion of duodenal mucosa was assessed both in animals and humans. The investigators reported an improvement in both glucose homeostasis and transaminases levels suggesting possibly an improvement of NASH.

Until now, lifestyle medication is the only recognized efficient treatment for fatty liver disease. Unfortunately, only a minority of patients achieve a significant weight loss and lifestyle modifications.

The investigators aim to study the duodenal mucosal resurfacing procedure in patients with NASH biopsy proven in a proof of concept study allowing to assess this technique as a potential treatment to NASH.

Design of study The study is designed as a single arm, proof of concept, non-randomized, open label trial to be conducted at one investigational site. All patients with biopsy proven NASH will undergo an upper endoscopy to perform a duodenal mucosal resurfacing procedure. Evolution of liver steatosis (assessed by MRI), insulin resistance (assessed by oral glucose tolerance test), liver damage (evaluated by blood tests), liver elastography (assessed by fibroscan, fibrotest), biometric parameters will be performed pre- and post-procedure.

Primary outcome :

• Feasability and safety of duodenal mucosal resurfacing, using Revita ™ duodenal mucosal resurfacing after submucosal injection, in patients with NASH.

Secondary outcomes:

• Evolution of steatosis assessed by MRI 6 months after the procedure.

• Evolution of liver fibrosis (assessed by Fibroscan, Fibrotest, Fibrosis four score (FIB-4) and NAFLD fibrosis score) at 6 and 12 months after the procedure.

• Evolution of liver tests at 6 and 12 months after the procedure.

• Evolution of insulin resistance at 1,3,6 and 12 months after the procedure.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: December 31, 2020
• Est. primary completion date: July 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 28 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Adult subjects (male and female), age 28 to 75 years.

2. NASH histological diagnosis according to the currently accepted definition of both EASL and AASLD, requiring the combined presence of steatosis (any degree> 5%) + lobular inflammation of any degree + liver cell ballooning of any amount, on a liver biopsy performed = 6 months before screening in the study and confirmed by central reading during the periode and (apendix 1)

1. SAF (steatosis, activity, fibrosis) activity score of 3 or 4 (>2)

2. SAF steatosis score = 1

3. SAF fibrosis score < 4

3. No other causes of chronic liver disease and compensated liver disease.

4. If applicable, have a type 2 diabetes with HbA1c <10.0 %

5. BMI (body mass index) = 24 and = 40 kg/m2.

6. Willing to sign an informed consent form.

7. Willing to comply with study requirements

Exclusion Criteria:

1. Evidence of another cause of liver disease.

2. History of sustained alcohol ingestion defined as: daily alcohol consumption > 30 g/day for males and > 20 g/day for females.

3. Previous gastrointestinal surgery such as subjects who have had Billroth 2, Roux-en-Y gastric bypass, or other similar procedures or conditions.

4. Known autoimmune disease, including celiac disease, or symptoms of systemic lupus eythematosus, sleroderma or other auto-immune connective tissue disorder.

5. For type 2 diabetes subjects, no current use of insulin or GLP-1 analogues.

6. Type 1 diabetes.

7. Probable insulin production failure defined as fasting C peptide serum < 1 ng/ml.

8. History of acute or chronic pancreatitis.

9. Active malignancy.

10. Persistent anemia defined as Hb < 10 g/dl.

11. Use of anticoagulation therapy which cannot be discontinued for 7 days before and 14 days after the procedure.

12. Use of P2Y12 inhibitors (clopidrogel, prasugrel, ticagrelor) which cannot be discontinued for 14 days before and14 days after the procedure.

13. History of coagulopathy or upper gastro-intestinal bleeding conditions likely to bleed.

14. Taking corticosteroids or drugs which possibly affect gastrointestinal motility or liver.

15. Unable to discontinue NSAIDs (non-steroidal anti- inflammatory drugs) during the treatment up to 4 weeks after procedure.

16. Use of weight loss medications.

17. Presence of liver cirrhosis (defined by histology)

18. Platelet count < 120 x 109/L.

19. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the presence of any of the following abnormalities:

20. Serum albumin < 32 g/L.

21. INR> 1.3.

22. Direct bilirubin> 1.3 mg/L.

23. ALT or AST > 5x ULN.

24. Alkaline Phosphatase > 3x ULN.

25. History of esophageal varices, ascites or hepatic encephalopathy.

26. Splenomegaly.

27. Human immunodeficiency virus.

28. Contraindications to MRI as defined below.

Related Conditions & MeSH terms

• Fatty Liver
• NASH - Nonalcoholic Steatohepatitis
• Non-alcoholic Fatty Liver Disease

Intervention

Device:
• DMR
Procedure: DMR Procedure The Fractyl DMR procedure using the Revita System utilizes an over the wire endoscopic approach to ablate the duodenum. The procedure may be completed in an endoscopic suite or in an operating room depending on the facilities and support at each investigative site. All subjects are monitored and anesthetized by conscious sedation per each facility's standard protocol. A full DMR procedure is defined as 5 complete ablations or 9 axial centimeters of circumferentially ablated tissue in the duodenum. Subjects who do not receive any ablations during the DMR procedure will be followed for safety through the 4 week visit and then discontinued from the study. Other Names: DMR Revita

Locations

Country	Name	City	State
Belgium	Erasme Hospital	Brussels

Sponsors (2)

Lead Sponsor	Collaborator
Erasme University Hospital	Fractyl Laboratories, Inc.

Country where clinical trial is conducted

Belgium, 

References & Publications (19)

Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013 Mar;58(3):593-608. doi: 10.1016/j.jhep.2012.12.005. Review. — View Citation

Boza C, Riquelme A, Ibañez 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. — View Citation

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterologyh. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012 Jun;142(7):1592-609. doi: 10.1053/j.gastro.2012.04.001. Epub 2012 May 15. Erratum in: Gastroenterology. 2012 Aug;143(2):503. — View Citation

Ferrannini E, Mingrone G. Impact of different bariatric surgical procedures on insulin action and beta-cell function in type 2 diabetes. Diabetes Care. 2009 Mar;32(3):514-20. doi: 10.2337/dc08-1762. Review. — View Citation

Gniuli D, Calcagno A, Dalla Libera L, Calvani R, Leccesi L, Caristo ME, Vettor R, Castagneto M, Ghirlanda G, Mingrone G. High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats. Diabetologia. 2010 Oct;53(10):2233-40. doi: 10.1007/s00125-010-1830-9. Epub 2010 Jun 30. — View Citation

Gollisch KS, Lindhorst A, Raddatz D. EndoBarrier Gastrointestinal Liner in Type 2 Diabetic Patients Improves Liver Fibrosis as Assessed by Liver Elastography. Exp Clin Endocrinol Diabetes. 2017 Feb;125(2):116-121. doi: 10.1055/s-0042-118961. Epub 2016 Dec 22. — View Citation

Hannah WN Jr, Harrison SA. Effect of Weight Loss, Diet, Exercise, and Bariatric Surgery on Nonalcoholic Fatty Liver Disease. Clin Liver Dis. 2016 May;20(2):339-50. doi: 10.1016/j.cld.2015.10.008. Epub 2016 Feb 17. Review. — View Citation

Higuera-de la Tijera F, Servín-Caamaño AI. Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets. World J Hepatol. 2015 Jun 8;7(10):1297-301. doi: 10.4254/wjh.v7.i10.1297. — View Citation

Klebanoff MJ, Corey KE, Chhatwal J, Kaplan LM, Chung RT, Hur C. Bariatric surgery for nonalcoholic steatohepatitis: A clinical and cost-effectiveness analysis. Hepatology. 2017 Apr;65(4):1156-1164. doi: 10.1002/hep.28958. Epub 2017 Feb 21. — View Citation

Klein S, Fabbrini E, Patterson BW, Polonsky KS, Schiavon CA, Correa JL, Salles JE, Wajchenberg BL, Cohen R. Moderate effect of duodenal-jejunal bypass surgery on glucose homeostasis in patients with type 2 diabetes. Obesity (Silver Spring). 2012 Jun;20(6):1266-72. doi: 10.1038/oby.2011.377. Epub 2012 Jan 19. — View Citation

Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, Raverdy V, Leteurtre E, Dharancy S, Louvet A, Romon M, Duhamel A, Pattou F, Mathurin P. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology. 2015 Aug;149(2):379-88; quiz e15-6. doi: 10.1053/j.gastro.2015.04.014. Epub 2015 Apr 25. — View Citation

Li Y, Jadhav K, Zhang Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochem Pharmacol. 2013 Dec 1;86(11):1517-24. doi: 10.1016/j.bcp.2013.08.015. Epub 2013 Aug 26. Review. — View Citation

Rajagopalan H, Cherrington AD, Thompson CC, Kaplan LM, Rubino F, Mingrone G, Becerra P, Rodriguez P, Vignolo P, Caplan J, Rodriguez L, Galvao Neto MP. Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study. Diabetes Care. 2016 Dec;39(12):2254-2261. Epub 2016 Aug 12. — View Citation

Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, Castagneto M, Marescaux J. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006 Nov;244(5):741-9. — View Citation

Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg. 2004 Jan;239(1):1-11. — View Citation

Schneck AS, Anty R, Patouraux S, Bonnafous S, Rousseau D, Lebeaupin C, Bailly-Maitre B, Sans A, Tran A, Gugenheim J, Iannelli A, Gual P. Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis. Front Physiol. 2016 Aug 19;7:344. doi: 10.3389/fphys.2016.00344. eCollection 2016. — View Citation

Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010 Nov;52(5):1836-46. doi: 10.1002/hep.24001. Review. — View Citation

Verdam FJ, Greve JW, Roosta S, van Eijk H, Bouvy N, Buurman WA, Rensen SS. Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab. 2011 Feb;96(2):E379-83. doi: 10.1210/jc.2010-1333. Epub 2010 Nov 17. — View Citation

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. Review. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety of duodenal mucosal resurfacing characterized by the incidence of all Adverse Device Effects (ADEs), and subsequent adverse events [ Time Frame: 12 months ] in patients with NASH.	Safety will be characterized by the incidence of all Adverse Device Effects (ADEs), non-serious and serious, possibly related to or related to the procedure and/or device that are experienced by study participants.; Safety evaluations will also be performed to ensure no subsequent adverse events have occurred and to ensure any adverse events during the trial that are considered on-going are stable or have resolved. Safety will be assessed at 1 and 6 months following the intervention.	12 months
Secondary	Change in Magnetic Resonance Fat Fraction (MRFF) from baseline in the following 6 months in DMR subjects.	Magnetic Resonance Fat fraction	baseline and 6 months post-procedure
Secondary	Change in NAS score from baseline in the following 12 months in DMR subjects.	Centrally scored histological improvement in NAFLD from baseline to the end of 12 months post-procedure, where improvement is defined as: No worsening in fibrosis; and; A decrease in NAFLD Activity Score (NAS) of at least 2 points	baseline and 12 months post-procedure
Secondary	Change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) from baseline in the following at 6 months in DMR subjects	Absolute change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) is a fibrosis marker. A score <1.45 has a negative predictive value of over 90% for advanced liver fibrosis. A score of >3.25 has a positive predictive value of 65% for advanced fibrosis with a specificity of 97%.	baseline and 6 months post-procedure
Secondary	Change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) from baseline in the following at 12 months in DMR subjects	Absolute change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) is a fibrosis marker. A score <1.45 has a negative predictive value of over 90% for advanced liver fibrosis. A score of >3.25 has a positive predictive value of 65% for advanced fibrosis with a specificity of 97%.	baseline and 12 months post-procedure
Secondary	Change in Transient Elastography using Firboscan from baseline in the following at 6 months in DMR subjects	Transient Elastography	baseline and 6 months post-procedure
Secondary	Change in Transient Elastography using Firboscan from baseline in the following at 12 months in DMR subjects	Transient Elastography	baseline and 12 months post-procedure
Secondary	Change in Magnetic Resonance Fat Fraction (MRFF) from baseline in the following 12 months in DMR subjects.	Magnetic Resonance Fat fraction	baseline and 12 months post procedure
Secondary	Change in transaminases levels from baseline in the following 6 months in DMR subjects	Transaminases levels	baseline and 6 months post-procedure
Secondary	Change in transaminases levels from baseline in the following 12 months in DMR subjects	Transaminases levels	baseline and 12 months post-procedure
Secondary	Change in Insulin resistance measured by oral glucose tolerance test (OGTT) from baseline in the following 6 months in DMR subjects	Insulin resistance as abnormal HOMA IR	baseline and 6 months post-procedure
Secondary	Change in Insulin resistance measured by oral glucose tolerance test (OGTT) from baseline in the following 12 months in DMR subjects	Insulin resistance as abnormal HOMA IR	baseline and 12 months post procedure
Secondary	Change in stage of fibrosis from baseline in the following 12 months in DMR subjects	Liver histology	baseline and 12 months post-procedure