Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease

Prior treatment

• Current or recent (\<6 months prior to enrollment) use of weight loss medication(s)
• Vitamin E supplementation or use of metformin
  • -washout period 30 days
• Previous bariatric surgery
• Prior use of empagliflozin
• Metal or magnetic implants, devices or objects inside of or on the body, which are not MRI compatible
• Recent initiation (\<3 months prior to enrollment) of anti-hypertensive or lipid medication(s)
• Females who are sexually active and not protects by an effective method of birth control (e.g. UID or medication or patch)
  • -can re-screen 30 days after getting on birth control
• Current or recent (\<6 months prior to enrollment) use of medication(s) associated with weight gain (e.g. atypical anti-psychotics).

Other illness

• History of significant alcohol intake or current use
• Diabetes (type 1 or 2)
• Lower limb infection/ulceration within 3 months of screening
• Structural and functional urogenital abnormalities, that predispose for urogenital infections
• Major psychiatric disorder
• Gilbert's Syndrome
• Any known causes of liver disease (except NAFLD and NASH)
• History of cancer
• Untreated thyroid disorder
• History of decompensation events (ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma)

Lab values

• ALT \> 250U/L at screening
• Impaired fasting glucose (\>100 mg/dL)
• 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)
• Platelets \< 150,000 cells/mm3
• Total bilirubin \> 1.3 mg/dL
• INR \> 1.3
• Albumin \<3.2 g/dL
• Significant renal dysfunction (estimated glomerular filtration rate \[eGFR\] \< 80 mL/min/1.73 m2),

Other

• Known hypothalamic or pituitary dysfunction
• Current pregnancy or plans to become pregnant
• Females unwilling to be tested for pregnancy
• Tobacco use
• Diagnosed monogenic obesity

• For clinical referral to screening visit:
• BMI \>30 kg/m2 or \>95th BMI-Percentile
• Weight Range of 75kg to 150kg
• Age 16 to \<21 at baseline
• Elevated alanine aminotransferase (ALT) more than twice the upper limit of normal by gender (≥ 44 U/L for girls, ≥ 50 U/L for boys)63 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 months of screening.
• History of lifestyle modification to treat obesity or NAFLD.
• Tanner stage \>2
• Normal fasting glucose (fasting blood glucose \<100 mg/dL)
  • To be obtained at screening visit:
• Confirmation of obesity;
• Tanner stage 2,3,4 or 5;
• Normal fasting glucose tolerance (fasting blood glucose \<100 mg/dL);
• 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 rescreened 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%
• Willingness to adhere to lifestyle considerations throughout the study