Fibrosis Reduction in Non Alcoholic Steatohepatitis (FRIN)

March 22, 2023 updated by: Mingrone Geltrude, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Fibrosis Reduction in Non Alcoholic Steatohepatitis: the Effects of Weight Loss vs Metabolic Surgery

Background: Non-Alcoholic Steatohepatitis (NASH) represents one of the stages of Non-Alcoholic Fatty Liver Disease (NAFLD) with a very high risk to evolve in cirrhosis and hepato-carcinoma.

Currently, the only diagnostic method is a liver biopsy that remains the gold standard for characterizing liver histologic alterations and fibrosis stages. There is no specific treatment for NASH, in fact no drugs are currently licensed specifically for treating this disease.

Aim: Our aim is to conduct a non-inferiority, randomized-controlled trial (RCT) comparing Roux-en-Y Gastric bypass (RYGB) with an intensive lifestyle modification plan (Very low-calorie diet, VLCD) for the reduction of advanced stages of fibrosis in subjects with obesity and NASH after 25% weight loss.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Materials and Methods: The Investigators will screen patients with obesity, NAFLD fibrosis score (NFS) >0.676 and FibroScan > 9.5 kPA who have a high probability of NASH with advanced stage of fibrosis.

Participants will undergo liver biopsy to make diagnosis according to the Steatosis Activity Fibrosis (SAF) score algorithm. Subjects with BMI ≥ 30 and ≤50 kg/m2, age 25-65 years and F3-F4 fibrosis stage at liver biopsy will be included and randomized 1:1 to RYGB or VLCD. Anthropometric parameters, body composition with DEXA and liver function with blood samples will be assessed at the enrolment. A mixed meal metabolic test will be also performed to evaluate insulin sensitivity and secretion. These procedures will be repeated after 25% weight loss. Expectation: The Investigators expect a reduction of 2 points of histological fibrosis after 25% weight loss following either metabolic surgery or dieting. The investigators foresee also reversal of NASH, improvement of metabolic syndrome and glycemic control, changes in insulin sensitivity and secretion, changes in lipid profile, in NASH liver markers, in Fibroscan variables and in body composition

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Roma, Italy, 00188
        • Mingrone Geltrude

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

25 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Informed Consent signed before starting any procedure foreseen by the study;
  • Liver Ultrasound shoving steatosis and Fibroscan>9,5 KPa;
  • NAFLD fibrosis score>0,676;
  • diagnosis of NASH with stage F3-F4 of fibrosis according to SAF score, documented by liver biopsy and no evidence of another form of liver disease;
  • BMI≥ 30 and ≤50 kg/m2;
  • Age 25-65 years.

Exclusion Criteria:

  • Chronic liver disease other than NAFLD (e.g. hemochromatosis, viral or autoimmune hepatitis, Wilson's disease, α1 -antitrypsin deficiency);
  • Presence of esophageal varices and/or ascites;
  • INR ≥ 1,4;
  • Platelet count ≤ 100000;
  • Substantial alcohol consumption (>20 g/day for women or >30 g/day for men) and/or toxin exposure;
  • Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous 6 months;
  • End stage renal failure;
  • Participation in any other concurrent therapeutic clinical trial;
  • Any other life-threatening, non-cardiac disease;
  • Pregnancy;
  • Type 1 diabetes, or LADA;
  • Lipodystrophy;
  • Abetalipoproteinemia;
  • Interfering medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids);
  • Inability to give informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: intensive lifestyle modifications
VLCD 800-850 Kcal/day
Dietary supplement: intensive life style modification
Weight loss will be induced using a VLCD (800-850 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber) with replacement meals for 2 months, followed by structured food reintroduction every 2-8 weeks (about 50% carbohydrate, 35% total fat, and 15% protein), and an ongoing structured program with follow-up visits up to 25% body weight loss
Active Comparator: Roux-en-y-gastric bypass
laparoscopic RYGB
Procedure: roux -en-y- gastric bypass
Roux-&-Y Gastric Bypass (RYGB) involves the use of a surgical stapler to create a small and vertically oriented gastric pouch with a volume of 30 ml. The upper pouch is completely divided by the gastric remnant and is anastomosed to the jejunum, 75 cm distally to the Treitz's ligament, through a narrow gastrojejunal anastomosis in a Roux-en-Y fashion. Bowel continuity is restored by an entero-entero anastomosis, between the excluded biliary limb and the alimentary limb, performed at 100 cm from the gastrojejunostomy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
histological reduction of fibrosis
Time Frame: 2 years
The primary outcome is the rate of histological reduction of 2 points of fibrosis after 25% weight loss following either metabolic surgery or dieting
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Liver histology
Time Frame: 2 years

Reversal of NASH: number of partcipant with a NAFLD activity score (NAS: from 0 to 8) < 3;

Changes in Fibroscan evaluation: number of participant with a FibroScan <9.5 kPa.
2 years
Liver Markers
Time Frame: 2 years
Changes in liver markers: number of participant with a significant reduction of AST and ALT from baseline;
2 years
Non-alcoholic Fatty Liver Disease Fibrosis score
Time Frame: 2 years
Changes in Non-alcoholic Fatty Liver Disease Fibrosis score from baseline
2 years
Fibrosis-4 (FIB-4) Index
Time Frame: 2 years
Changes in Fibrosis-4 (FIB-4) Index for Liver Fibrosis from baseline;
2 years
Fibroscan
Time Frame: 2 years
Changes in Fibroscan evaluation: number of participant with a FibroScan <9.5 kPa.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Investigators

  • Principal Investigator: geltrude mingrone, professor, Policlinico A. Gemelli IRCCS

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2021

Primary Completion (Anticipated)

September 1, 2025

Study Completion (Anticipated)

September 1, 2026

Study Registration Dates

First Submitted

February 16, 2023

First Submitted That Met QC Criteria

March 22, 2023

First Posted (Actual)

April 4, 2023

Study Record Updates

Last Update Posted (Actual)

April 4, 2023

Last Update Submitted That Met QC Criteria

March 22, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4103

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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