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Effect of DMR in the Treatment of NASH (DMR_NASH_001)

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ClinicalTrials.gov Identifier: NCT03536650
Recruitment Status : Recruiting
First Posted : May 25, 2018
Last Update Posted : May 28, 2018
Sponsor:
Collaborator:
Fractyl Laboratories, Inc.
Information provided by (Responsible Party):
Erasme University Hospital

Tracking Information
First Submitted Date  ICMJE April 13, 2018
First Posted Date  ICMJE May 25, 2018
Last Update Posted Date May 28, 2018
Actual Study Start Date  ICMJE November 8, 2017
Estimated Primary Completion Date June 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 14, 2018)
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. [ Time Frame: 12 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03536650 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2018)
  • Change in Magnetic Resonance Fat Fraction (MRFF) from baseline in the following 6 months in DMR subjects. [ Time Frame: baseline and 6 months post-procedure ]
    Magnetic Resonance Fat fraction
  • Change in NAS score from baseline in the following 12 months in DMR subjects. [ Time Frame: baseline and 12 months post-procedure ]
    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
  • Change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) from baseline in the following at 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    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%.
  • Change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) from baseline in the following at 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    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%.
  • Change in Transient Elastography using Firboscan from baseline in the following at 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    Transient Elastography
  • Change in Transient Elastography using Firboscan from baseline in the following at 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    Transient Elastography
  • Change in Magnetic Resonance Fat Fraction (MRFF) from baseline in the following 12 months in DMR subjects. [ Time Frame: baseline and 12 months post procedure ]
    Magnetic Resonance Fat fraction
  • Change in transaminases levels from baseline in the following 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    Transaminases levels
  • Change in transaminases levels from baseline in the following 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    Transaminases levels
  • Change in Insulin resistance measured by oral glucose tolerance test (OGTT) from baseline in the following 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    Insulin resistance as abnormal HOMA IR
  • Change in Insulin resistance measured by oral glucose tolerance test (OGTT) from baseline in the following 12 months in DMR subjects [ Time Frame: baseline and 12 months post procedure ]
    Insulin resistance as abnormal HOMA IR
  • Change in stage of fibrosis from baseline in the following 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    Liver histology
Original Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2018)
  • Change in Magnetic Resonance Fat Fraction (MRFF) from baseline in the following 6 months in DMR subjects. [ Time Frame: baseline and 6 months post-procedure ]
    Magnetic Resonance Fat fraction
  • Change in NAS score from baseline in the following 12 months in DMR subjects. [ Time Frame: baseline and 12 months post-procedure ]
    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
  • Change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) from baseline in the following at 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    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%.
  • Change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) from baseline in the following at 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    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%.
  • Change in Transient Elastography using Firboscan from baseline in the following at 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    Transient Elastography
  • Change in Transient Elastography using Firboscan from baseline in the following at 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    Transient Elastography
  • Change in Magnetic Resonance Fat Fraction (MRFF) from baseline in the following 12 months in DMR subjects. [ Time Frame: baseline and 12 months post procedure ]
    Magnetic Resonance Fat fraction
  • Change in transaminases levels from baseline in the following 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    Transaminases levels
  • Change in transaminases levels from baseline in the following 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    Transaminases levels
  • Change in Insulin resistance from baseline in the following 6 months in DMR subjects [ Time Frame: baseline and 6 months post-procedure ]
    Insulin resistance
  • Change in Insulin resistance from baseline in the following 12 months in DMR subjects [ Time Frame: baseline and 12 months post procedure ]
    Insulin resistance
  • Change in stage of fibrosis from baseline in the following 12 months in DMR subjects [ Time Frame: baseline and 12 months post-procedure ]
    Liver histology
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of DMR in the Treatment of NASH
Official Title  ICMJE Evaluation of Duodenal Mucosal Resurfacing (DMR) for the Treatment of Non Alcoholic Steatohepatitis (NASH), a Proof of Concept Study
Brief 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.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE NASH - Nonalcoholic Steatohepatitis
Intervention  ICMJE 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

Other Name: Revita
Study Arms  ICMJE Experimental: DMR procedure
Intervention: Device: DMR
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 14, 2018)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2019
Estimated Primary Completion Date June 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 28 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alia Hadefi, MD +3225553714 alia.hadefi@erasme.ulb.ac.be
Contact: Christophe Moreno, PhD, MD +3225553714 christophe.moreno@erasme.ulb.ac.be
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03536650
Other Study ID Numbers  ICMJE P2017/302
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Erasme University Hospital
Study Sponsor  ICMJE Erasme University Hospital
Collaborators  ICMJE Fractyl Laboratories, Inc.
Investigators  ICMJE
Principal Investigator: Jacques Deviere, PhD, MD Erasme Hospital
PRS Account Erasme University Hospital
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP