Bariatric Surgery Versus Non-alcoholic Steato-hepatitis (BRAVES)

• ClinicalTrials.gov Identifier: NCT03524365
• Recruitment Status: Active, not recruiting
• First Posted: May 14, 2018
• Last Update Posted: April 8, 2021
• Sponsor: Catholic University of the Sacred Heart
• Collaborator: University of Roma La Sapienza
• Information provided by (Responsible Party): Geltrude Mingrone, Catholic University of the Sacred Heart

Study Description

Brief Summary:

Bariatric-metabolic surgery is effective in treating the cluster of conditions forming the metabolic syndrome, strictly associated with NAFLD and NASH. Recently, we and other authors have shown also in the long term (up 5 years) with randomized-controlled trials (RCTs) that bariatric-metabolic surgery allows remission of type 2 diabetes and obesity reduction, which are the two major pathogenetic factors of NASH development, with maintenance of weight loss.

Few small and mainly retrospective studies have shown that bariatric surgery is effective in improving NASH histologic picture in obese subjects.

The aim of our proposal is to conduct a 3 arm single centre, superiority, RCT comparing Roux-en-Y Gastric Bypass (RYGB) with Sleeve Gastrectomy (SG) and with Intensive Lifestyle Modifications (ILM) for the treatment of Non-Alcoholic Steato-Hepatitis.

Condition or disease	Intervention/treatment	Phase
Non Alcoholic Steatohepatitis	Procedure: RYGB; Procedure: SG; Other: Intensive Lifestyle Modification	Not Applicable

Detailed Description:

This is a Randomized Controlled multicentre Trial involving the Catholic University (Professor Geltrude Mingrone as PI and Professor Marco Raffaelli as co-PI)

The research question in PICOT format (P) - Population: Adults 25 to 65 years of age and BMI ≥ 30 and ≤40 kg/m2 with histological diagnosis of NASH. Subjects with normal liver who underwent laparoscopic elective cholecystectomy, but otherwise in healthy conditions, will be used as controls for the discovery of non-invasive biomarkers.

(I) - Intervention: Roux-en-Y Gastric Bypass or Sleeve Gastrectomy, both plus lifestyle counseling.

(C) - Comparison: Intensive Lifestyle Modifications. (O) - Outcome: the histological resolution of NASH without worsening of fibrosis at 1 year after the interventions.

(T) - Time: One year after the intervention started.

1.3.3.2 Research Goals

• The primary aim of our study is to assess the effects of bariatric-metabolic surgery or ILM on NASH at 1 year after the interventions.
• Secondary aims are to assess the safety of bariatric surgery and the improvement of liver fibrosis, CVD, insulin sensitivity, T2DM, lipoprotein profile, NASH markers and fecal microbiota at 1 year and the follow up of NASH markers up to 2 years, and to obtain a non-invasive score systems to make diagnosis of NASH.

Research outcomes

• The primary outcome is the histological resolution of NASH without worsening of fibrosis at 1 year after the interventions.

• The secondary outcomes are :

  1. Adverse health events including the need for re-operation
  2. Changes in liver fibrosis
  3. Changes in glycemic control (only in diabetic patients)
  4. Changes in cardiovascular risk score
  5. Changes in insulin sensitivity and secretion
  6. Changes in food intake
  7. Changes in physical activity
  8. Changes in quality of life
  9. Changes in gut microbiota
  10. Changes in body composition: Fat-Free Mass (FFM), Fat Mass (FM).
  11. Discovery of non-invasive biomarkers for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis

The changes in NASH liver markers will be investigated at 1, and 2 years follow-up.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 288 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Study on the Effects of Roux-en-Y Gastric Bypass Versus Sleeve Gastrectomy or Intensive Lifestyle Modifications on Non Alcoholic Steato-Hepatitis
• Actual Study Start Date: December 6, 2018
• Estimated Primary Completion Date: April 2022
• Estimated Study Completion Date: September 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: RYGB plus LM counselling; 96 subjects with NASH	Procedure: RYGB; 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. Lifestyle modification counselling is provided to each patient.
Active Comparator: SG plus LM counselling; 96 subjects with NASH	Procedure: SG; The SG is created using a linear stapler with two sequential 4.8/60-mm green load firings for the antrum, followed by two or three sequential 3.5/60-mm blue loads for the remaining gastric corpus and fundus. The stapler is applied alongside a 48-Fr calibrating bougie. The resection line is performed avoiding the ''critical area'' by resecting the fundus 1.5 cm from the angle of His. Staple lines are buttressed with bovine pericardial strips. The resected stomach is grasped at the antral tip by a laparoscopic grasper and retrieved through one of the trocar sites. A methylene blue dye test by a nasogastric tube is routinely performed at the end of the procedure. The residual gastric remnant capacity is 60-80 ml. Drains are not routinely placed, and the nasogastric tube is removed at the end of the procedure. Upper gastrointestinal contrast (Gastrografin) study is performed on the first postoperative day. Lifestyle modification counselling is provided to each patient.
Sham Comparator: ILM; 96 subjects with NASH	Other: Intensive Lifestyle Modification; Resting calorie requirements will be calculated via the Harris Benedict equation (24) and an activity factor, and subjects will be instructed not to change their activity level other than that suggested by physicians during the study. The diet will contain 1/3 kcal less than the calculated energy expenditure and 30% fat of which 10% saturated, 55% lower glycemic index carbohydrates and 15% proteins. The participants will be encouraged to gradually increase their walking to achieve 10,000 steps per day. A moderate intensity physical activity program of 1 hour of aerobic exercise 2-3 hours per week will be recommended to all subjects. Their physical activity will be assessed by IPAQ-SF as reported below.

Outcome Measures

Primary Outcome Measures :

1. histological resolution of NASH without worsening of fibrosis at 1 year after the interventions [ Time Frame: 1 year ]
   histological evaluation of liver biopsy, The diagnosis of non-alcoholic steato hepatitis (NASH) on liver biopsies will be made using the NAFLD Activity Score (NAS) that is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3) and the steatosis activity and fibrosis (SAF) score algorithm (The SAF scores steatosis (0-3), ballooning degeneration (0-2), lobular inflammation (0-2), and fibrosis (0-4)).

Secondary Outcome Measures :

1. Adverse health events including the need for re-operation [ Time Frame: 1 year ]
   adverse events include early operation complications
2. Changes in the presence of histological liver fibrosis [ Time Frame: 1 year ]
   liver fibrosis will be examined in liver biopsies
3. Changes in glycemic control (only in diabetic patients) [ Time Frame: 1 year ]
   diabetes remission or improvement of glycemic control (glycated hemoglobin HbA1c)
4. Changes in cardiovascular risk score [ Time Frame: 1 year ]
   total cardiovascular risk score is computed by the Framingham risk
5. Changes in insulin sensitivity [ Time Frame: 1 year ]
   euglycemic clamp for insulin sensitivity
6. Changes in food intake [ Time Frame: 1 year ]
   food intake diary
7. Changes in physical activity [ Time Frame: 1 year ]
   Physical activity questionnaire
8. Changes in quality of life [ Time Frame: 1 year ]
   RAND 36-Item Short Form Health Survey questionnaire
9. Changes in gut microbiota [ Time Frame: 1 year ]
   gut microbiota will be measured
10. Changes in body composition: Fat-Free Mass (FFM), Fat Mass (FM). [ Time Frame: 1 year ]
    FFM and FM will be assessed by DEXA
11. NASH resolution at 3 years [ Time Frame: 3 years ]
    Liver biopsy histology
12. NASH resolution at 5 years [ Time Frame: 5 years ]
    Liver biopsy histology
13. Non-invasive biomarkers for the diagnosis of NASH [ Time Frame: 1 year ]
    Blood-based biomarkers panel for non-invasive diagnosis of NASH and liver fibrosis
14. Elastography [ Time Frame: 5 years ]
    To measure shear wave propagation through liver parenchyma

Eligibility Criteria

• Ages Eligible for Study: 25 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects with NASH documented by liver biopsy and no evidence of another form of liver disease with a BMI ≥ 30 and ≤55 kg/m2.

Subjects with normal liver who underwent laparoscopic elective cholecystectomy, but otherwise in healthy conditions, will be used as controls for the discovery of non-invasive biomarkers.

Exclusion Criteria:

• Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous 6 months; Liver cirrhosis; End stage renal failure; Participation in any other concurrent therapeutic clinical trial; Any other life-threatening, non-cardiac disease; Pregnancy; Inability to give informed consent; Substantial alcohol consumption (>20 g/day for women or >30 g/day for men); Wilson's disease; Lipodystrophy; Parenteral nutrition; Abetalipoproteinemia; Interfering medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids).

Contacts and Locations

Locations

Italy

San Camillo

Roma, Italy

University of Rome Sapienza

Roma, Italy

Catholic University School of Medicine

Rome, Italy, 00168

Sponsors and Collaborators

Catholic University of the Sacred Heart

University of Roma La Sapienza

Investigators

• Principal Investigator: Geltrude Mingrone, MD PhD; Catholic University

More Information

• Responsible Party: Geltrude Mingrone, Associate Professor of Internal Medicine, Catholic University of the Sacred Heart
• ClinicalTrials.gov Identifier: NCT03524365
• Other Study ID Numbers: 20182004
• First Posted: May 14, 2018
• Last Update Posted: April 8, 2021
• Last Verified: April 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases