Clinical trial NCT03867487: SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty Liver Disease
Official title: SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty Liver Disease
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Non-Alcoholic Fatty Liver Disease
NAFLD
Pediatric NAFLD
Lead sponsor: Ann & Robert H Lurie Children's Hospital of Chicago
Sponsor class: OTHER
First posted: 2019-03-08
Enrollment: 40
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Efficacy as Measured by Change in Hepatic Fat Fraction (HFF)
timeFrame: Baseline to 26 weeks
Secondary outcomes:
measure: Change in Body Measurements: Body mass index (BMI)
timeFrame: Baseline to 26 weeks
measure: Change in Body Measurements: Body Fat %
timeFrame: Baseline to 26 weeks
measure: Change in Body Measurements: Visceral Fat %
timeFrame: Baseline to 26 weeks
measure: Change in Biomarkers of NAFLD: Alanine transaminase (ALT)
timeFrame: Baseline to 26 weeks
measure: Change in Biomarkers of NAFLD: Cytokeratin (CK)-18
timeFrame: Baseline to 26 weeks
measure: Change in Blood Pressure
timeFrame: Baseline to 26 weeks
measure: Change in Arterial Stiffness
timeFrame: Baseline to 26 weeks
measure: Change in Glycemic Control
timeFrame: Baseline to 26 weeks
measure: Change in Proton Density Fat Fraction (PDFF) from MRI
timeFrame: Baseline to 26 weeks
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Ann & Robert H Lurie Children's Hospital of Chicago
state: Illinois
Study officials:
affiliation: Ann & Robert H Lurie Children's Hospital of Chicago
name: Justin Ryder, PhD
role: PRINCIPAL_INVESTIGATOR
References: