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

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ClinicalTrials.gov Identifier: NCT03524365
Recruitment Status : Recruiting
First Posted : May 14, 2018
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
Geltrude Mingrone, Catholic University of the Sacred Heart

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: ILM 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) 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.

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

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

(T) - Time: One year after 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). The changes in NASH liver markers will be investigated at 1, and 2 years follow-up.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : September 2021
Estimated Study Completion Date : September 2025


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: ILM

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.





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 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



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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 ≤40 kg/m2.

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03524365


Contacts
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Contact: Geltrude Mingrone, MD PhD 00390630154395 geltrude.mingrone@unicatt.it
Contact: Esmeralda Capristo, MD 00390630154903 esmeralda.capristo@policlinicogemelli.it

Locations
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Italy
Catholic University School of Medicine Recruiting
Rome, Italy, 00168
Contact: Geltrude Mingrone, MD    00390630154395    geltrude.mingrone@unicatt.it   
Principal Investigator: Geltrude Mingrone, MD         
Sponsors and Collaborators
Catholic University of the Sacred Heart
Investigators
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Principal Investigator: Geltrude Mingrone, MD PhD Catholic University

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Responsible Party: Geltrude Mingrone, Associate Professor of Internal Medicine, Catholic University of the Sacred Heart
ClinicalTrials.gov Identifier: NCT03524365     History of Changes
Other Study ID Numbers: 20182004
First Posted: May 14, 2018    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: December 2018

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

Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases