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

Overview

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.

Detailed description

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.

Interventions

• Drug Empagliflozin 10 MG
  Participants will take a 10 mg oral tablet of empagliflozin, an orally-active inhibitor of sodium-glucose co-transporter 2 (SGLT2)
• Drug Placebo Oral Tablet
  Participants will take an identical appearing oral tablet with zero active ingredient.

Primary outcome measures

• Efficacy as Measured by Change in Hepatic Fat Fraction (HFF) [Time frame: Baseline to 26 weeks]

Secondary outcome measures (9)

• Change in Body Measurements: Body mass index (BMI) [Time frame: Baseline to 26 weeks]
• Change in Body Measurements: Body Fat % [Time frame: Baseline to 26 weeks]
• Change in Body Measurements: Visceral Fat % [Time frame: Baseline to 26 weeks]
• Change in Biomarkers of NAFLD: Alanine transaminase (ALT) [Time frame: Baseline to 26 weeks]
• Change in Biomarkers of NAFLD: Cytokeratin (CK)-18 [Time frame: Baseline to 26 weeks]
• Change in Blood Pressure [Time frame: Baseline to 26 weeks]
• Change in Arterial Stiffness [Time frame: Baseline to 26 weeks]
• Change in Glycemic Control [Time frame: Baseline to 26 weeks]
• Change in Proton Density Fat Fraction (PDFF) from MRI [Time frame: Baseline to 26 weeks]

Eligibility criteria

Inclusion criteria

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

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
• Previous bariatric surgery
• Use of metformin
• 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 protected by an effective method of birth control (e.g. IUD or medication or patch)
• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Ann & Robert H Lurie Children's Hospital of Chicago — Chicago

Identifiers

NCT: NCT03867487 · IRB 2023-6034

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗