BRAVES: Bariatric Surgery Versus Non-alcoholic Steato-hepatitis
Study Details
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 |
|---|---|---|
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N/A |
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
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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.
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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
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The primary outcome is the histological resolution of NASH without worsening of fibrosis at 1 year after the interventions.
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The secondary outcomes are :
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Adverse health events including the need for re-operation
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Changes in liver fibrosis
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Changes in glycemic control (only in diabetic patients)
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Changes in cardiovascular risk score
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Changes in insulin sensitivity and secretion
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Changes in food intake
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Changes in physical activity
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Changes in quality of life
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Changes in gut microbiota
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Changes in body composition: Fat-Free Mass (FFM), Fat Mass (FM).
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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
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.
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| 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.
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| 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.
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Outcome Measures
Primary Outcome Measures
- histological resolution of NASH without worsening of fibrosis at 1 year after the interventions [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
- Adverse health events including the need for re-operation [1 year]
adverse events include early operation complications
- Changes in the presence of histological liver fibrosis [1 year]
liver fibrosis will be examined in liver biopsies
- Changes in glycemic control (only in diabetic patients) [1 year]
diabetes remission or improvement of glycemic control (glycated hemoglobin HbA1c)
- Changes in cardiovascular risk score [1 year]
total cardiovascular risk score is computed by the Framingham risk
- Changes in insulin sensitivity [1 year]
euglycemic clamp for insulin sensitivity
- Changes in food intake [1 year]
food intake diary
- Changes in physical activity [1 year]
Physical activity questionnaire
- Changes in quality of life [1 year]
RAND 36-Item Short Form Health Survey questionnaire
- Changes in gut microbiota [1 year]
gut microbiota will be measured
- Changes in body composition: Fat-Free Mass (FFM), Fat Mass (FM). [1 year]
FFM and FM will be assessed by DEXA
- NASH resolution at 3 years [3 years]
Liver biopsy histology
- NASH resolution at 5 years [5 years]
Liver biopsy histology
- Non-invasive biomarkers for the diagnosis of NASH [1 year]
Blood-based biomarkers panel for non-invasive diagnosis of NASH and liver fibrosis
- Elastography [5 years]
To measure shear wave propagation through liver parenchyma
Eligibility Criteria
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
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | San Camillo | Roma | Italy | ||
| 2 | University of Rome Sapienza | Roma | Italy | ||
| 3 | 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 20182004