SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty Liver Disease

Prior treatment

• Current or recent (\<6 months prior to enrollment) use of weight loss medication(s)
• 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)
• Current pregnancy or plans to become pregnant
  • Females unwilling to be tested for pregnancy
  • Females who are sexually active and not protected by an effective method of birth control (e.g. IUD or medication or patch)
• 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

• Vitamin E supplementation
• Use of metformin
• Known hypothalamic or pituitary dysfunction
• Tobacco use
• Diagnosed monogenic obesity

• For clinical referral to screening visit:
• Age: 12 to \<20 years old
• Diagnosis of Obesity: BMI-percentile \>95th (using age- and sex- based Center for Disease Control definitions) or BMI ≥30 kg/m2
• 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
• History of lifestyle modification to treat obesity or NAFLD
  • 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 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%
• Willingness to adhere to lifestyle considerations throughout the study