Gemcabene for the Treatment of Pediatric NAFLD
Gemcabene for the Treatment of Pediatric NAFLD
This is a multicenter, prospective, open-label, Phase 2, proof of concept study to test
 preliminary efficacy and safety of gemcabene in children with established nonalcoholic fatty
 liver disease (NAFLD) incompletely treated by lifestyle changes. The hypothesis of the study
 is that 300 mg of gemcabene once a day for 12 weeks will reduce alanine aminotransferase
 (ALT), hepatic steatosis, dyslipidemia and down regulate de novo lipogenesis in children with
 NAFLD.
Nonalcoholic fatty liver disease (NAFLD) has quickly become the most common liver disease in
 children in the US and is rising worldwide. While the true prevalence and incidence are not
 known, estimates have placed prevalence in the US as high as 7 million children. The
 prevalence varies greatly across race and ethnic groups with Hispanic, Asian and White
 children having increased rates compared to African American children. Lifestyle changes are
 the first line treatment, but many children fail to respond to these. Pharmaceutical
 treatments are needed for children that cure NAFLD and ideally also benefit the systemic
 features (dyslipidemia, insulin sensitivity, BMI). Gemcabene calcium (Gemcabene) is a
 promising therapeutic that may benefit pediatric NAFLD and early phase trials are needed to
 support further development for this indication. It has several mechanisms of action
 including enhancing the clearance of very-low-density lipoprotein (VLDL) and blocking the
 production of hepatic triglyceride and cholesterol synthesis. Gemcabene was previously tested
 in adults for treatment of dyslipidemia and has extensive safety data.

 In this study, 40 children ages 12-17 years with histologically confirmed NAFLD or MRI based
 diagnosis and elevated ALT will receive 300 mg of gemcabene per day for 12 weeks. Study
 visits will occur at screening, baseline, week 2, week 6 and week 12. A follow up phone call
 will occur one month after the child stops taking the study medication.
Inclusion Criteria:

 1. Provision of signed and dated informed consent form

 2. Provision of signed and dated assent, if indicated

 3. Stated willingness to comply with all study procedures and availability for the
 duration of the study

 4. Children aged 12-17 years at the time of informed consent

 5. History of clinical diagnosis of NAFLD including a, b and c below:

 1. Medical history eliminating, other chronic liver diseases (for example
 mitochondrial diseases, hepatotoxic drugs, anorexia nervosa)

 2. Laboratory studies: negative testing for hepatitis C and normal ceruloplasmin

 3. Either liver biopsy confirming NAFLD or MRI > 10% steatosis within the past three
 years

 6. ALT ≥ 54 U/L for boys or ≥ 46 U/L for girls and ≤ 250 U/L at screening visit and
 within past three months (prior to screening). If ALT at screening is more than two
 times the historic value (or a historic value is not available), the subject will be
 asked to repeat the ALT after four weeks. If the repeat ALT is more than 50% increased
 or decreased over the screening ALT a third ALT may 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.

 7. Body weight ≥ 60 kg at the time of screening

 8. Able to take oral medication and be willing to adhere to the study drug regimen

 9. Minimum of three months of attempted lifestyle modification to treat the NAFLD and
 agreement to adhere to Lifestyle Considerations (dietary improvement and physical
 activity) throughout study duration

 Exclusion Criteria:

 1. Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias)

 2. Seizure disorder

 3. Active coagulopathy (international normalized ratio (INR) > 1.4)

 4. Renal dysfunction with an estimated glomerular filtration rate (eGFR) <60ml/min/1.73
 calculated using Schwartz Bedside GFR calculator for children

 5. History of active malignant disease requiring chemotherapy or radiation

 6. History of significant alcohol intake (AUDIT questionnaire) or inability to quantify
 alcohol consumption

 7. Use of new medications or supplements with the intent to treat NAFLD/nonalcoholic
 steatohepatitis (NASH) during the 30 days prior to screening, including statin
 therapy. Medications or supplements (including metformin and vitamin E) that they have
 been on and are on a stable dose are acceptable

 8. History of bariatric surgery or planning to undergo bariatric surgery during study
 duration

 9. Clinically significant depression

 10. Any girl nursing, planning a pregnancy, known or suspected to be pregnant, or who has
 a positive pregnancy screen

 11. Non-compensated liver disease defined as cirrhosis and any one of the following
 hematologic, biochemical, and serological criteria on entry into protocol:

 -  Hemoglobin < 10 g/dL;

 -  White blood cell (WBC) < 3,500 cells/mm3;

 -  Neutrophil count < 1,500 cells/mm3;

 -  Platelets < 150,000 cells/mm3;

 -  Total bilirubin > 1.3 mg/dL unless due to Gilbert's syndrome (subjects with a
 history of Gilbert's syndrome may be included if both direct bilirubin and the
 reticulocyte count do no exceed the upper limit of normal (ULN) [reflexive direct
 bilirubin testing will be used to confirm Gilbert's syndrome])

 -  Albumin < 3.2 g/dL

 -  INR > 1.3

 -  Abnormal alkaline phosphatase

 -  Any history of ascites, variceal bleeding, hepatic encephalopathy, or
 hepatocellular carcinoma (HCC)

 12. Poorly controlled diabetes mellitus (hemoglobin A1c (HbA1c) > 8%) or requiring insulin

 13. Patients with type I diabetes mellitus

 14. Chronic liver disease other than NAFLD

 15. Patients on Cytochrome P450 3A4 (CYP3A4) inhibitors such as itraconazole or macrolide
 antibiotics are excluded

 16. Patients who are on thiazolidinediones, fibrates or fish oils are excluded

 17. Patients who are on daily prescription medications are excluded except for allergy
 medications, Attention Deficit Hyperactivity Disorder (ADHD) medications, asthma
 medications, or any other acceptable medication in the opinion of the investigator

 18. Abnormal creatinine kinase levels at screening (may be repeated if the elevation is
 thought to be exercise related)

 19. Sexually active female participants of childbearing potential and Tanner stage ≥ 4 or
 menstruating unwilling to utilize two acceptable forms of contraception from screening
 through completion of the study or unwilling to complete pregnancy tests throughout
 the study

 20. Currently enrolled in a clinical trial or who received an investigational study drug
 within 90 days of screening

 21. Participants who are not able or willing to comply with the protocol or have any other
 condition that would impede compliance or hinder completion of the study, in the
 opinion of the investigator