Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease

Summary

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.

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

* ALT \> 250U/L at screening
* History of significant alcohol intake or current use
* Impaired fasting glucose (\>100 mg/dL)
* Diabetes (type 1 or 2)
* 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
* Lower limb infection/ulceration within 3 months of screening
* Metal or magnetic implants, devices or objects inside of or on the body, which are not MRI compatible
* Structural and functional urogenital abnormalities, that predispose for urogenital infections
* Recent initiation (\<3 months prior to enrollment) of anti-hypertensive or lipid medication(s)
* Major psychiatric disorder
* Known hypothalamic or pituitary dysfunction
* Current pregnancy or plans to become pregnant
* Females unwilling to be tested for pregnancy
* 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
* Tobacco use
* 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
* Gilbert's Syndrome
* Any known causes of liver disease (except NAFLD and NASH)
* Significant renal dysfunction (estimated glomerular filtration rate \[eGFR\] \< 80 mL/min/1.73 m2),
* Diagnosed monogenic obesity
* History of cancer
* Untreated thyroid disorder
* History of decompensation events (ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma)
* Current or recent (\<6 months prior to enrollment) use of medication(s) associated with weight gain (e.g. atypical anti-psychotics).

Conditions2

Locations1 site

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