Vertical Sleeve Gastrectomy and Lifestyle Modification for the Treatment of Non-Alcoholic Steatohepatitis

The pilot study proposed in this protocol will determine whether patients with a BMI of
30-39.9 kg/m2 will consent to liver biopsy, accept randomization to VSG, participate in
lifestyle modification for a one-year period and consent to a paired liver biopsy at 12
months. Sixty candidates will be biopsied with 42 randomizations within the first year
yielding 19 (including dropouts) participants/group. This should be sufficient to further
estimate meaningful differences in liver histology given the estimated weight loss of
lifestyle modification with and without VSG and a correlation of percent weight loss and
histological score improvement over the short term (12 months). Determining the impact of the
VSG is essential for expanding the traditional indications for bariatric surgery and thus,
broadening the potential impact of this pilot study.

The investigators will screen patients by telephone between the ages of 40 and 67 with a
self-reported BMI of 30-39.9 kg/m2, a history of prediabetes, or type 2 diabetes. Prospective
participants will be asked to provide a copy of their most recent liver chemistries to see if
the AST or ALT fall in the inclusion range. The investigators will screen for a history of
alcohol or other substance abuse and a surgical history that would preclude a safe VSG.
Prospective participants will be invited to attend a seminar. They will be instructed to keep
a food and exercise log for two weeks and return for a second visit. After consent is signed,
during the eligibility review period participants will have their height and weight recorded,
history reviewed, liver function tests, HbA1c, a urine sample, a basic metabolic profile, and
INR will be obtained at this time and the participant will be referred for a liver biopsy. If
the biopsy is consistent with NASH with a NAS >=5, then the participant will undergo MRI
assessment and serum markers for inflammation. Vital signs (pulse, temperature, respiration,
blood pressure, weight and BMI) will be obtained at each study visit. Participants will then
begin an 800 calorie per day diet for 7 days during which they will receive their
randomization assignment to VSG or not; all participants will receive lifestyle modification
as the investigators need to see if surgery can provide any additional benefit to lifestyle
modification. A basic metabolic panel will be performed at the conclusion of the 800 calorie
diet. VSG will be performed laparoscopically and the greater curvature resected 6 cm for the
pylorus to the angle of His over a 40 French Bougie. Lifestyle modification can begin
immediately after surgery, though the VSG participants will not have calorie limits until 6
months after surgery. Participants will be seen regularly by the hepatologist and surgeon at
1 week, 4 weeks, 12 weeks, 6 months, and 12 months. Lifestyle modification will be overseen
by Nancy Sherwood, Ph.D. Lifestyle will be delivered on an individual basis once per week for
the first 6 months, twice per month for the next 3 months, and monthly up to one year.
Vitamins A, B1, B12 and D and a comprehensive metabolic panel including liver chemistries
will be performed at 3 months and 12 months in both groups. At 12 months a repeat liver
biopsy will be performed (participants will have the opportunity to select an alternative
approach if they did not have a good experience with the initial liver biopsy in order to
ensure a paired specimen). This decision will be made in conjunction with the interventional
radiologist. MRI for steatosis and elasticity will be performed and serum inflammatory and
fibrosis markers will be obtained at 12 months as well as the collection of another urine
sample. Participants will exit the study but will continue usual care after 12 months. We
will create a biorepository for stool samples to measure the microbiome and for remaining
liver tissue to measure the transcriptome.

Participants meeting study entry criteria are randomized with equal probability to one of two
study groups: (1) Lifestyle modification (LSM) or (2) Vertical Sleeve Gastrectomy (VSG + LSM)
with Iifestyle modification, followed for 12 months. The primary goal for the trial is to
determine if we can recruit, randomize, and retain participants to perform invasive and
non-invasive measurements of NASH and fibrosis, deliver lifestyle modification and
demonstrate the safety of VSG. The investigators wish to also understand which of these two
interventions is more effective in achieving, 12 months after entry into the trial, a
reduction in NAS composed of the non-weighted scores: (1) steatosis 0-3 (2) Inflammation 0-3
and (3) ballooning 0-2. Secondary goals include comparing the two treatment groups for
changes in other measured outcomes including MRI assessments of intrahepatic triglyceride and
liver elasticity and serum markers. As a pilot study, a sample size of 19 in each group
should offer significant information as to the difference in NAS score reduction between to
two groups and achieve adequate power to distinguish clinically significant changes in the
primary and secondary outcome measures. These data support the overarching objective i.e. to
provide evidence that a larger, longer-term clinical outcomes trial is feasible. A goal is
for a longer term follow up for 5 years to assess the durability of treatment effects and
treatment differences.

Inclusion Criteria:

1. Age 40 to 67 years at eligibility visit.

2. Diagnosed with T2DM (type 2 diabetes mellitus) or prediabetes for at least 6 months
prior to enrollment, under the active care of a doctor for at least the six months
prior to enrollment, HbA1c< 9% and NOT requiring insulin.

3. AST >32 IU/L or an ALT>39.9 IU/L

4. Body Mass Index (BMI): 30.0-39.9 kg/m2 at eligibility visit.

5. Willingness to accept random assignment to either treatment group.

6. All patients must have insurance with no exclusion for obesity related treatments or
management of obesity surgery complications. This applies to all participants enrolled
in the study

7. Expect to live or work within approximately one-hour traveling time from the study
clinic for the duration of the one-year trial.

8. Willingness to comply with the follow-up protocol and successful completion of the
run-in (described below).

9. Written informed consent.

Exclusion Criteria:

1. Cardiovascular event (myocardial infarction, acute coronary syndrome, coronary artery
angioplasty or bypass, stroke) in the past six months.

2. Current evidence of congestive heart failure, angina pectoris, or symptomatic
peripheral vascular disease.

3. Cardiac stress test indicating that surgery would not be safe.

4. Pulmonary embolus or thrombophlebitis in the past six months.

5. Cancer of any kind (except basal cell skin cancer or cancer in situ) unless documented
to be disease-free for five years.

6. Significant anemia (hemoglobin 1.0 g/dL or more below normal range) or history of
coagulopathy.

7. Serum creatinine >1.5 mg/dL.

8. Serum total bilirubin greater than the upper limit of normal in the absence of
Gilbert's syndrome, or alkaline phosphatase or ALT or AST greater than twice the upper
limit of normal. Elevated INR.

9. Alcohol intake more than one drink or >20 grams per day

10. History of stomach surgery, bile duct surgery, pancreatic surgery, splenectomy, or
colon resection.

11. Gastric or duodenal ulcer in the past six months.

12. History of intra-abdominal sepsis (except for uncomplicated appendicitis or
diverticulitis more than six months prior to enrollment).

13. Previous organ transplantation.

14. Self-reported HIV-positive status, active tuberculosis, active malaria, chronic
hepatitis B or C, cirrhosis, or inflammatory bowel disease.

15. Currently pregnant or nursing, or planning to become pregnant in the next two years.

16. History of alcohol, drug, or opioid dependency (excluding nicotine) in the past five
years.

17. Active psychosocial or psychiatric problem that is likely to interfere with adherence
to the protocol.

18. Depression: A CES-D score more than 17.

19. Current participation in a conflicting research protocol.

20. Presence of any chronic or debilitating disease that would make adherence to the
protocol difficult.

21. 12-lead EKG indicating that surgery would not be safe.

22. Serum c-peptide <1.0 ng/ml post prandial.

23. Exclusions may also be made at the discretion of the attending physician or the
eligibility committee.

24. Contraindication to MRI scanning. MRI contraindications are assessed by MR
technologists on the day of scanning using a standard safety screening form.

25. Gastroesophageal reflux disease requiring medications. History of endoscopy
demonstrating esophagitis or Barrett's changes in the esophagus. Any history of
dysphagia.

26. More than 2 cups of coffee per day.