Metabolic Surgery for Steato-Hepatitis (MeSH)

March 4, 2020 updated by: King's College London

Metabolic Surgery for the Treatment and Understanding of Non-Alcoholic Steato-Hepatitis (NASH): Weight-Dependent and Weight-Independent Effects

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes mellitus (T2DM) and is characterised by excess liver fat on imaging or histology. NAFLD affects up to 25% of the Western population. It's more aggressive form is non-alcoholic steatohepatitis (NASH) characterised by cell injury, inflammation and fibrosis, and is associated with increased mortality from liver and cardiovascular disease. Currently, there is no specific treatment for NASH. Diet and exercise-induced weight loss remain the only recommended options. However, maintaining weight loss in the long term is difficult. There is therefore a significant unmet need for effective therapy in patients with NASH that can address the underlying mechanisms of disease. Although preliminary observational evidence suggests that bariatric/metabolic surgery, especially RYGB can improve NASH, no controlled trials to date has confirmed the efficacy of surgery compared to standard weight loss programs. Also, while animal and clinical studies have shown that bariatric surgery exerts weight-independent effects on glucose metabolism, it is yet unknown if the observed effects of bariatric/metabolic surgery on NASH are due to weight loss alone or result from additional, weight-independent mechanisms, like in the case of T2DM. If the effect of surgery on inflammation, liver fibrosis and other mechanisms of cardiometabolic risk were found to be independent on weight reduction, there would be profound and far-reaching implications for both the treatment and the understanding of NASH, cardiovascular disease and obesity-related cancers.

This project will investigate the hypothesis that, similarly to surgical control of diabetes, bariatric/metabolic surgery can also exert weight-independent effects on mechanisms of disease in NAFLD/NASH (i.e. influence on lowgrade inflammation and markers of fibrosis)

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

This study's population includes patients with severe obesity (BMI >35kg/m2 or >32.5. kg/m2 if patient of South Asian, Caribbean or Black ethnicity) and non-alcoholic fatty liver disease (NAFLD) who are eligible for bariatric/metabolic surgery and are on the waiting list for either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at King's College Hospital. Patients who meet study criteria will be assigned to the study groups as described below:

  1. Surgery Group: Fourteen patients who meet study criteria will be assigned to the study group and will undergo surgery; 7 RYGB and 7 SG, as planned for their standard care.
  2. Lifestyle Intervention Group: Fourteen patients matched to the surgery group for age, gender, BMI, diabetes status, and NAFLD score will undergo additional lifestyle interventions, dietary counselling (either a meal replacement diet or a low calorie diet) by a dietician aimed at inducing at least a 5-7% weight reduction, prior to their surgery (while on the waiting list for surgery).

Each participant in both the surgery and lifestyle intervention group will then attend the baseline visit.

At the baseline visit the participant will undergo a metabolic lab panel from bloods already provided to the clinic. This visit will also involve the clinical team performing an ultrasound-guided fine needle aspiration (FNA) of the liver. The fine needle aspiration will involve inserting a small needle through the skin to take a small sample of cells from the liver. It will be carried out in the Institute of Liver Studies at King's College Hospital. The clinical research team will also access the participants medical record to collect data from your medical history including weight, height, body mass index (BMI) and previous FibroScan®. Additionally, a saliva swab, urine and stool sample will be collected.

A subgroup of patients (6 participants in the Lifestyle Intervention Group, 6 undergoing RYGB, 6 undergoing SG) will undergo a mixed meal test (MMT) to investigate changes in meal-response of circulating cardiometabolic markers, bile acids and gut hormone as well as calculated insulin sensitivity/secretion. The surgery group patients will undergo surgery as per standard practice and will be reviewed in the bariatric clinic 4-6 weeks' post surgery- this will be at 5-7% weight loss (WL). At the 5-7% WL visit the patient will undergo a metabolic lab panel, a liver FNA, will have their weight and height recorded and BMI calculated. A new FibroScan will be performed.

Additionally, a saliva swab, urine and stool sample will be collected. The 12 patients ( 6 RYGB, 6 SG) in the surgery group who were included in the previous MMT will undergo a second MMT to investigate the change in meal-response of circulating cardio-metabolic markers, bile acids, gut hormones, insulin sensitivity/secretion post-surgery.

The lifestyle intervention group participants will attend a one-to-one dietary consultation with a registered dietician to select a diet plan: either a low-calorie diet or meal replacement diet to induce 5-7% WL. Information booklets that will aid dieting will be provided to the participant. The participant will then be expected to follow the dietary advice in order to achieve a 5-7% WL. The clinical research team will provide additional phone call consultations at 2-, 4-, 8-, 12-, 14-, 16-, 18-, 20-, 22-, 24-weeks post-lifestyle intervention to assess weight change, diet adherence and motivation. Once the participant has a 5-7% WL they will attend the bariatric clinic for their 5-7% WL visit. At the 5-7% WL visit the patient will undergo a metabolic lab panel, a liver FNA, will have their weight and height recorded and BMI calculated. A new FibroScan will be performed. Additionally, a saliva swab, urine and stool sample will be collected. The 6 patients in the lifestyle intervention group who were included in the previous MMT will undergo a second MMT to investigate the change in meal-response of circulating cardio-metabolic markers, bile acids, gut hormones, insulin sensitivity/secretion post-lifestyle intervention.

The outcome measures above will be measured at two time-points; baseline and after 5-7% weight loss in both groups. The study design allows to control for weight loss (through an equivalent weight loss of 5-7% between the two groups) and to understand the effects bariatric/metabolic surgery versus lifestyle intervention (diet and exercise), by mechanisms independent of weight-loss, on markers of NASH and cardiovascular risk, therefore allowing to identify weight-independent effects of bariatric/metabolic surgery, if they exist. Based on published data it is predicted that it will take 3-6 months for patients to achieve 5-7% weight loss (WL) from the lifestyle intervention used in this study and 4-6 weeks after surgery.

Adipose and liver tissue from intraoperative biopsies and gastric and intestinal tissue from surgical waste will be collected and stored for future ethically approved research.

Study Type

Interventional

Enrollment (Anticipated)

28

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

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

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

• BMI greater than 35 kg/m2 (or >32.5. kg/m2 for patients of South Asian, Caribbean or Black ethnicities) with raised alanine transaminase (ALT), aspartate transaminase (AST) and a FibroScan® score > 7.9 (indicating presence of NAFLD and high likelihood of NASH).

Exclusion Criteria:

  • other causes of liver disease such as viral, alcoholic (alcohol consumption >20 g/day for women or >30 g/day for men),
  • auto-immune disease
  • use of certain medications that may interfere with outcome measures (i.e. corticosteroids, insulin and glycoprotein-1 (GLP-1) analogues).

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: surgery group
Fourteen patients who meet study criteria will be assigned to the study group and will undergo surgery; 7 RYGB and 7 SG, as planned for their standard care.
Procedure: Metabolic/Bariatric surgery
Patients will undergo surgery; 7 RYGB and 7 SG, as planned for their standard care.
Active Comparator: lifestyle and diet
Fourteen patients matched to the surgery group for age, gender, BMI, diabetes status, and NALFD score will undergo additional lifestyle interventions, dietary counselling and or meal replacement by a dietician aimed at inducing at least a 5-7% weight reduction, prior to their surgery (while on the waiting list for surgery).
Other: Lifestyle and Diet
Patients will be provided with a lifestyle interventions including dietary counselling choosing between a Low-Calorie Diet or a Meal Replacement Diet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of liver inflammation and fibrosis
Time Frame: Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
Markers of liver injury in blood [i.e. CK-18, tissue inhibitor of metalloproteinases (TIMP-1) amino-terminal pro-peptide of type III collagen (PIIINP), hyaluronic acid].
Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
Assessment of liver inflammation and fibrosis
Time Frame: Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
Serum adipokines [i.e. adiponectin, visfatin, IL-6, TNFa].
Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
Assessment of liver inflammation and fibrosis
Time Frame: Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
FibroScan® score
Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
Assessment of liver inflammation and fibrosis
Time Frame: Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)
Fine Needle Aspiration of the liver to obtain a measurement of inflammatory cells in liver
Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of markers of cardiovascular disease in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)
Time Frame: Changes from 0 to 30 and 60 minutes after meal consumption.

Serum levels of apoprotein (apolipoproteins; apoprotein C3, apoprotein C2, and apoprotein E). Blood will be obtained at 0, 30 and 60 minutes.

• Bile acids: Blood will be obtained at 0, 30 and 60 minutes. Adipose and liver tissue from intraoperative biopsies; gastric and intestinal tissue from surgical waste will be collected. Furthermore, urine, saliva and stool will be obtained at baseline and at 5-7% WL to be stored for use in future downstream hypothesis.
Changes from 0 to 30 and 60 minutes after meal consumption.
Assessment of gut hormones in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)
Time Frame: Changes from -10 minutes to 0, 15, 30, 60, 90, 120 and 180 minutes after meal consumption.
Plasma levels gut hormones [i.e.GLP-1, PYY3-36, ghrelin, glucose, insulin, c-peptide levels] will be measured.
Changes from -10 minutes to 0, 15, 30, 60, 90, 120 and 180 minutes after meal consumption.
Assessment of insulin sensitivity in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)
Time Frame: Changes from -10 minutes to 0, 15, 30, 60, 90, 120 and 180 minutes after meal consumption.
Oral glucose insulin sensitivity (OGIS) index will be used to calculate insulin sensitivity.
Changes from -10 minutes to 0, 15, 30, 60, 90, 120 and 180 minutes after meal consumption.
Assessment of bile acids in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)
Time Frame: Changes from 0 to 30 and 60 minutes after meal consumption.
Measurement of bile acids in blood.
Changes from 0 to 30 and 60 minutes after meal consumption.

Collaborators and Investigators

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

Sponsor

King's College London

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)

February 13, 2020

Primary Completion (Anticipated)

March 30, 2021

Study Completion (Anticipated)

January 1, 2022

Study Registration Dates

First Submitted

September 20, 2019

First Submitted That Met QC Criteria

February 20, 2020

First Posted (Actual)

February 24, 2020

Study Record Updates

Last Update Posted (Actual)

March 5, 2020

Last Update Submitted That Met QC Criteria

March 4, 2020

Last Verified

September 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 267076

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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