Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease (SHIELD)

Justin Ryder

Status and phase: Enrolling; Phase 2

Conditions: Non-Alcoholic Fatty Liver Disease

Treatments: Drug: Placebo Oral Tablet; Drug: Empagliflozin 10 MG

Study type: Interventional

Funder types: Other

Identifiers

NCT06355310

IRB 2023-6429

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 16 to 20 years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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40 participants in 2 patient groups, including a placebo group

Study intervention

Experimental group

Description:

Empagliflozin 10 mg will be taken daily

Treatment:

Drug: Empagliflozin 10 MG

Control arm

Placebo Comparator group

Description:

Placebo oral tablet will be taken daily

Treatment:

Drug: Placebo Oral Tablet