Gemcabene for the Treatment of Pediatric NAFLD | NCT03436420

Name	Class
Gemphire Therapeutics	INDUSTRY

Description Module

Detailed Description

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.

Label	Type	Description	Intervention Names
Gemcabene	Experimental	Children receiving 12 weeks of treatment with gemcabene	Drug: Gemcabene

Name	Type	Description	Arm Group Labels	Other Names
Gemcabene	Drug	Participants will take 300 milligrams (mg) of gemcabene, once per day for 12 weeks.	Gemcabene

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percent Change in Alanine Aminotransferase (ALT)	Percent change in alanine aminotransferase (ALT) from baseline to 12 weeks was examined. ALT elevation is the most common screening test used for detecting NAFLD. The normal range for ALT varies by age, sex, and the specific assay used but is approximately 9-23 units/Liter (U/L) for boys and girls aged 1-18. Children with a sustained ALT ≥ 80 U/L are twice as likely to have nonalcoholic steatohepatitis (NASH), which is a severe form of NAFLD characterized by inflammation and liver cell damage.	Baseline, Week 12

Secondary Outcomes

Measure	Description	Time Frame
Absolute Change in ALT	Absolute change in ALT among study participants is reported here. ALT elevation is the most common screening test used for detecting NAFLD. ALT elevation is the most common screening test used for detecting NAFLD. The normal range for ALT varies by age, sex, and the specific assay used but is approximately 9-23 U/L for boys and girls aged 1-18. Children with a sustained ALT ≥ 80 U/L are twice as likely to have nonalcoholic steatohepatitis (NASH), which is a severe form of NAFLD characterized by inflammation and liver cell damage.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provision of signed and dated informed consent form
Provision of signed and dated assent, if indicated
Stated willingness to comply with all study procedures and availability for the duration of the study
Children aged 12-17 years at the time of informed consent
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
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.
Body weight ≥ 60 kg at the time of screening
Able to take oral medication and be willing to adhere to the study drug regimen
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:

Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias)
Seizure disorder
Active coagulopathy (international normalized ratio (INR) > 1.4)
Renal dysfunction with an estimated glomerular filtration rate (eGFR) <60ml/min/1.73 calculated using Schwartz Bedside GFR calculator for children
History of active malignant disease requiring chemotherapy or radiation
History of significant alcohol intake (AUDIT questionnaire) or inability to quantify alcohol consumption
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
History of bariatric surgery or planning to undergo bariatric surgery during study duration
Clinically significant depression
Any girl nursing, planning a pregnancy, known or suspected to be pregnant, or who has a positive pregnancy screen
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)
Poorly controlled diabetes mellitus (hemoglobin A1c (HbA1c) > 8%) or requiring insulin
Patients with type I diabetes mellitus
Chronic liver disease other than NAFLD
Patients on Cytochrome P450 3A4 (CYP3A4) inhibitors such as itraconazole or macrolide antibiotics are excluded
Patients who are on thiazolidinediones, fibrates or fish oils are excluded
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
Abnormal creatinine kinase levels at screening (may be repeated if the elevation is thought to be exercise related)
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
Currently enrolled in a clinical trial or who received an investigational study drug within 90 days of screening
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

ID	Term
D065626	Non-alcoholic Fatty Liver Disease
D008107	Liver Diseases
D009765	Obesity

ID	Term
D005234	Fatty Liver
D004066	Digestive System Diseases
D050177	Overweight
D044343	Overnutrition