Gemcabene for the Treatment of Pediatric NAFLD
Condition: Non-Alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Gemcabene
Intervention description: Participants will take 300 milligrams (mg) of gemcabene, once per day for 12 weeks.
Intervention MeSH terms: Calcium
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 12 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Pediatrics; Lipids; Liver Diseases; Obesity

Summary:

      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.
    

Eligibility criteria:

        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