Controlled Trial of WLS vs. CLI for Severely Obese Adolescents With NASH

The investigators have designed a rigorously controlled study designed to evaluate NASH
outcomes in two parallel cohorts: 1) severely obese adolescents with NASH who have chosen to
undergo WLS (specifically VSG) for clinical indications compared to 2) a control group of
severely obese adolescents with NASH enrolled in a CLI offered as part of this study. The
study will provide the best evidence to date of the effectiveness of WLS and CLI in treating
NASH in adolescents with body mass index (BMI) ≥ 35 kg/m2. The investigators will also
concurrently collect health-care utilization data to enable subsequent cost-effectiveness
analyses (CEA) to evaluate the cost-effectiveness of WLS vs. CLI intervention in
severely-obese adolescents with NASH. If the investigators' data support our hypothesis that
WLS yields superior results, this will set the stage for randomized studies (if needed) and
translational studies of weight loss-independent biological mechanism(s) unique to WLS, which
may include specific changes in bile acid signaling and in the intestinal microbiome. The
latter would facilitate developing novel pharmacotherapies accessible to younger or less
obese children with NASH to whom WLS is not applicable. Cumulatively, this study has the
potential to yield significant improvements in medical and quality of life (QOL) outcomes for
a large proportion of pediatric patients with NASH and to reduce long term health care costs
by identifying effective treatment options and decreasing progression to cirrhosis and
end-stage liver disease.

Inclusion Criteria:

- Adolescents ages 12-19 years (range as defined by World Health Organization).

- BMI ≥ 35 to 69 kg/m2 (minimum BMI per current guidelines for WLS in adolescents). An
upper limit of BMI was set to avoid rare outliers in BMI.

- Meet current standard of care eligibility criteria for adolescent WLS.

- Liver biopsy for clinical indication to evaluate for NASH within 1 year of enrollment.
Biopsy must confirm definite or borderline NASH with a minimum histological NASH
Activity Score of ≥ 3.

- No evidence of any other liver disease by history, screening tests or histological
evaluation.

- Written informed consent from parent/legal guardian and informed assent from the
adolescent

Exclusion Criteria:

- Evidence of other chronic liver disease: autoimmune hepatitis; hepatitis B; hepatitis
C; hemochromatosis; alpha-1-antitrypsin (A1AT) deficiency; Wilson disease; use of
medications known to cause fatty liver for > 2 consecutive weeks in past year (i.e.
systemic glucocorticoids, tetracycline, anabolic steroids, valproic acid); alcohol
intake >10 gm/day females & >20 gm/day males.

- Non-compensated liver disease with any of the following: hemoglobin <10 g/dL; white
blood cell count <3,500 cells/mm3, platelet count <130,000 cells/mm3 of blood, direct
bilirubin >1.0 mg/dL, total bilirubin >3 mg/dL, albumin <3.2 g/dL, international
normalized ratio (INR) >1.4

- Active psychiatric disorder that would prevent eligibility for WLS or impede adherence
to CLI, including clinically significant depression (hospitalization or suicidal
ideation) in past 12 months.

- Any medical condition preventing eligibility for WLS including but not limited to
micronutrient deficiencies (e.g. iron) refractory to medical therapy or inflammatory
bowel disease.

- Poorly controlled Type 2 diabetes mellitus (T2DM) defined as hemoglobin A1C (HgbA1c) >
10%.

- Initiation of high dose vitamin E (>400 IU per day) or other medications which could
alter NASH histology at any time after baseline liver biopsy or during the trial.
Stable dose of vitamin E that was started 12 months or more prior to biopsy is
allowed.

- Weight reduction of >5% between baseline liver biopsy and enrollment, as weight loss
>5% may change NASH severity.

- Inability or failure to provide informed assent/consent

- Current enrollment in another clinical trial or receipt of an investigational study
drug within 6 months prior to the baseline liver biopsy

- Any female who is currently nursing, planning a pregnancy, known or suspected to be
pregnant, or has a positive pregnancy screen

- Inability to travel to study site at intervals necessary for clinical interventions
(CLI or WLS).

- Prior history of WLS.