Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease

Non-Alcoholic Fatty Liver Disease Clinical Trial

— SHIELD  

Official title:

Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06355310
• Other study ID #: IRB 2023-6429
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 20, 2024
• Est. completion date: December 31, 2028

Study information

• Verified date: April 2024
• Source: Ann & Robert H Lurie Children's Hospital of Chicago
• Contact: Angie Figueroa, MS
• Phone: 773-550-0749
• Email: SHIELD[@]luriechildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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, 2-stage clamp (overnight Stay),Stable isotope tracers (overnight Stay), MRI scan (MRS-Liver), BMI/anthropometrics, urine pregnancy test for female participants, iDXA scan (body fat and bone density), arterial stiffness and blood pressure.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 20 Years

Eligibility

Inclusion Criteria:

• For clinical referral to screening visit:
• BMI >30 kg/m2 or >95th BMI-Percentile
• 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
• 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)
• 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).

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

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)
• Placebo Oral Tablet
Participants will take an identical appearing oral tablet with zero active ingredient.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Ann & Robert H Lurie Children's Hospital of Chicago

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hepatic Fat	change in hepatic fat fraction (Hepatic fat will be measured by MRI via proton density fat fraction (PDFF)) from baseline (first measurement time point) to 26-weeks.	26-Weeks
Secondary	Body mass index	BMI; body fat% (total and visceral fat); ALT; biomarkers of NAFLD oCK-18 ototal and activated PAI-1 oIL-8; biomarkers of bone health (additional safety outcome) oN-terminal collagen type I extension propeptide (PINP) oOsteocalcin oC-terminal cross-linking telopeptide of type I collagen (CTX); Systolic and diastolic blood pressure; glycemic control (from oral glucose tolerance test); Insulin sensitivity (from oral glucose tolerance test) by the whole-body insulin sensitivity index	26-Weeks