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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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NAFLD, Non-Alcoholic Fatty Liver Disease, Pediatric NAFLD

Intervention / Treatment
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* Drug: Empagliflozin 10 MG
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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 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 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) 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] < 90 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)

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study intervention<br>Empagliflozin 10 mg will be taken daily | Drug: Empagliflozin 10 MG<br>* Participants will take a 10 mg oral tablet of empagliflozin, an orally-active inhibitor of sodium-glucose co-transporter 2 (SGLT2)<br>* Other names: Jardiance;|
| Placebo Comparator: Control arm<br>Placebo oral tablet will be taken daily | Drug: Placebo Oral Tablet<br>* Participants will take an identical appearing oral tablet with zero active ingredient.<br>* Other names: Control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Measured by Change in Hepatic Fat Fraction (HFF) | HFF is measured by MRI via 1H- magnetic resonance spectroscopy (MRS). HFF will be measured with single-voxel 1H-MRS on a 3.0 T Trio whole body MRI scanner, using the software package provided by the vendor. The MR elastography measurement will consist of a phase-contrast 2D GRE scan (TR/TE = 50/25 ms, matrix 256 x 90, GRAPPA R=3, slice thickness 7mm) with motion encoding in the z-direction, and acoustic excitation at 60 Hz. Four axial slices will be acquired, each with a single breath-hold. Manual ROIs covering the liver will be drawn on the stiffness maps (in kPa units) generated by the system software. Fibrosis staging will be determined following previously published guidelines. | Baseline to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Measurements: Body mass index (BMI) | Height and weight will be measured using a calibrated, wall-mounted stadiometer and an electronic scale, respectively. Three consecutive height and weight measurements will be obtained and averaged. BMI will be calculated as the weight in kilograms divided by the height in meters, squared. | Baseline to 26 weeks | 
| Change in Body Measurements: Body Fat % | Total percent body fat mass and lean muscle mass will be determined by dual energy x-ray absorptiometry (iDXA, GE Healthcare). Body fat percentage is calculated by body fat mass divided by the sum of fat and lean masses. | Baseline to 26 weeks | 
| Change in Body Measurements: Visceral Fat % | Total body fat mass and visceral fat mass will be determined by dual energy x-ray absorptiometry (iDXA, GE Healthcare). Visceral fat percentage of total body mass is calculated by visceral fat mass divided by the sum of total fat and lean masses. Visceral fat percentage of total fat mass is calculated by visceral fat mass divided by total fat mass. | Baseline to 26 weeks | 
| Change in Biomarkers of NAFLD: Alanine transaminase (ALT) | Fasting (≥12 hours) blood will be collected for the measurement of ALT at Fairview Diagnostics Laboratories, Fairview-University Medical Center, Minneapolis, MN - a Center for Disease Control and Prevention certified laboratory. | Baseline to 26 weeks | 
| Change in Biomarkers of NAFLD: Cytokeratin (CK)-18 | Fasting plasma samples will be used to measure CK-18 via Luminex Multiplex platform (Millipore, St. Louis, MO). | Baseline to 26 weeks | 
| Change in Blood Pressure | Blood pressure measurements will be obtained manually on the same arm using the same cuff size and equipment. Standardized procedures will be employed as described in previously published standards. Individual cuff size will be determined by measuring the arm circumference midway between the acromial process and the bony olecranon. Sitting blood pressure and heart rate will be measured after the participant has been resting quietly without legs crossed for 10 minutes. Measurements will be made three consecutive times (3-minute intervals). The final two of three independent measurements will be averaged. | Baseline to 26 weeks | 
| Change in Arterial Stiffness | Carotid- and femoral artery augmentation index and carotid-femoral pulse wave velocity (PWV) will be measured by the SphygmoCor® MM3 system (AtCor Medical, Sydney, Australia). Augmentation index is a measure of the relative magnitude of the reflected (or retrograde) pulse wave early in the cardiac cycle. Higher values of augmentation index represent increased arterial stiffening. PWV will be calculated as distance divided by transit time. Since pulse wave transit time decreases in stiffer arterial segments, higher values of pulse wave velocity represent increased arterial stiffness. | Baseline to 26 weeks | 
| Change in Glycemic Control | After fasting measures are completed, we will perform a 2-hour oral glucose tolerance test with fasting (-15 and 0-min) and serial postprandial (15-, 30-, 45-, 60-, 90-, and 120-minutes) plasma concentrations of glucose (glucose oxidase, YSI INC., Yellow Sprigs, OH) and insulin (ELISA, ALPCO Diagnostics, Windham, NH) measured after administration of a 75g glucose challenge. Samples will be batched and a stored for analysis at the completion of the study. Insulin sensitivity will be estimated by the whole-body insulin sensitivity index (WBISI) using plasma glucose and insulin concentrations. | Baseline to 26 weeks | 
| Change in Proton Density Fat Fraction (PDFF) from MRI | A proton density fat fraction (PDFF) image will be acquired using LiverLab's qdixon imaging acquisition (3D gradient echo, TR=9ms, flip angle=4°, TE=1.15, 2.46, 3.69, 4.92, 6.15, 7.38 ms, 2x2x3.5mm resolution, one 17s breath-hold). The MRS measurement of HFF will be used as the primary metric. As a secondary endpoint we will use PDFF which has shown promise as a measure of fibrosis staging compared to liver biopsy in children. | Baseline to 26 weeks |