SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty Liver Disease
SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty Liver Disease
This study is a randomized, double-blind, placebo-controlled trial specifically designed to
 evaluate the preliminary feasibility, initial efficacy and safety of SGLT2 inhibitors for
 treating NAFLD in adolescents with obesity.
The overall aim of this pilot study is to evaluate the feasibility and obtain a preliminary
 estimate of efficacy and safety of the SGLT2 inhibitor, empagliflozin, in adolescents with
 obesity (BMI-percentile ≥95th) who have MRI-confirmed NAFLD (hepatic fat fraction ≥ 5.5%) and
 have normal fasting glucose.

 Participants will take empagliflozin, once daily, in the morning, with or without food, in
 addition to receiving lifestyle/behavioral counseling throughout the study.

 The following data will be collected throughout the course of the study: Physical exam with
 tanner staging, safety and fasting labs, fasting blood draw (biomarkers), urine sample, stool
 sample, OGTT, CGM sensor placement and removal, MRI scan (MRS-Liver), BMI/anthropometrics,
 urine pregnancy test for female participants, iDXA scan (body fat and bone density), arterial
 stiffness and blood pressure.
Inclusion Criteria:

 For clinical referral to screening visit:

 1. Age: 12 to <20 years old

 2. Diagnosis of Obesity: BMI-percentile ≥95th (using age- and sex- based Center for
 Disease Control definitions) or BMI ≥30 kg/m2

 3. Elevated alanine aminotransferase (ALT) more than twice the upper limit of normal by
 gender (≥44 U/L for girls, ≥50 U/L for boys) within 3 months prior to screening (used
 for historic ALT value) OR diagnosis of NAFLD from ultrasound, MRI, or participants
 with biopsy-proven NASH within 12 moths of screening

 4. History of lifestyle modification to treat obesity or NAFLD

 To be obtained at screening visit:

 1. Confirmation of Obesity

 2. Tanner stage 2

 3. Normal fasting glucose tolerance (fasting blood glucose <100 mg/dL)

 4. If Screening ALT is used as inclusion criteria [if > 2x historic ALT value (historical
 value obtained clinically within 12 months of screening visit), repeated after 4 weeks
 [unable to randomize until completed]]. If the repeat ALT is more than 50% increased
 or decreased over the screening ALT, a third ALT should be obtained. If a third ALT is
 not within 50% of the previous value, then the subject is ineligible but may be
 screened at a later date. If ALT is not used:

 -  An ultrasound will be done to diagnose NAFLD if the diagnosis has not previously
 been made by ultrasound, MRI or biopsy

 -  A MRI-derived HFF ≥ 5.5%

 5. Willingness to adhere to lifestyle considerations throughout the study

 Exclusion Criteria:

 1. ALT > 250U/L at screening

 2. History of significant alcohol intake or current use

 3. Impaired fasting glucose (>100 mg/dL)

 4. Diabetes (type 1 or 2)

 5. Current or recent (<6 months prior to enrollment) use of weight loss medication(s)

 6. Vitamin E supplementation

 7. Previous bariatric surgery

 8. Use of metformin

 9. Prior use of empagliflozin

 10. Lower limb infection/ulceration within 3 months of screening

 11. Metal or magnetic implants, devices or objects inside of or on the body, which are not
 MRI compatible

 12. Structural and functional urogenital abnormalities, that predispose for urogenital
 infections

 13. Recent initiation (<3 months prior to enrollment) of anti-hypertensive or lipid
 medication(s)

 14. Major psychiatric disorder

 15. Current pregnancy or plans to become pregnant.Females unwilling to be tested for
 pregnancy. Females will be tested for pregnancy. Females who are sexually active and
 not protected by an effective method of birth control (e.g. UID or medication or
 patch)

 16. Tobacco use

 17. Significant liver dysfunction (levels >5 times the upper limit of normal (ULN)):

 ALT (ULN = 50 U/L) AST (ULN = 48 U/L) GGT (ULN = 48 U/L) ALP (ULN = 115 U/L)

 18. Platelets < 150,000 cells/mm3

 19. Total bilirubin 1.3 mg/dL

 20. INR 1.3

 21. Albumin <3.2 g/dL

 22. Gilbert's Syndrome

 23. Any known causes of liver disease (except NAFLD and NASH)

 24. Significant renal dysfunction (estimated glomerular filtration rate [eGFR] < 90
 mL/min/1.73 m2),

 25. Diagnosed monogenic obesity

 26. History of cancer

 27. Untreated thyroid disorder

 28. History of decompensation events (ascites, variceal bleeding, hepatic encephalopathy,
 or hepatocellular carcinoma)

 29. Current or recent (<6 months prior to enrollment) use of medication(s) associated with
 weight gain (e.g. atypical anti-psychotics)