Gemcabene for the Treatment of Pediatric NAFLD

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Gemcabene for the Treatment of Pediatric NAFLD: A Phase 2a Study

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Gemcabene


Participation Criteria
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Eligibility Criteria
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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: Medical history eliminating, other chronic liver diseases (for example mitochondrial diseases, hepatotoxic drugs, anorexia nervosa) Laboratory studies: negative testing for hepatitis C and normal ceruloplasmin 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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcabene<br>Children receiving 12 weeks of treatment with gemcabene | Drug: Gemcabene<br>* Participants will take 300 milligrams (mg) of gemcabene, once per day for 12 weeks.<br>* Other names: Gemcabene calcium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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. | Baseline, Week 6, Week 12 | 
| Percent Change in ALT Between Study Visits | Percent change in ALT from baseline to week 6 and the mean of week 6 and week 12 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 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 6, Week 12 | 
| Absolute Change in Hepatic Steatosis | Hepatic steatosis (fat accumulation in the liver) was measured by MRI using liver fat fraction (HepaFat-Scan by Resonance Health). NAFLD is characterized by an accumulation of fat in the liver. Having a fat percentage greater than 5% of the weight of the liver is a typical cut point to indicate NAFLD. The HepaFat-Scan software is a non-invasive method of measuring the volumetric liver fat fraction and is validated in children. | Baseline, Week 12 | 
| Absolute Change in Pancreatic Fat | Pancreatic fat was measured by MRI (HepaFat). Increased pancreatic fat is associated with more severe liver disease in children with NAFLD. | Baseline, Week 12 | 
| Absolute Change in Aspartate Aminotransferase (AST) | AST is a common screening test used for detecting NAFLD. The normal range for AST varies by age, sex, and the specific assay used but is approximately 13-32 U/L for boys and 12-24 units/Liter for girls aged 7-18. Elevated AST levels indicate increased liver disease. | Baseline, Week 6, Week 12 | 
| Change in Fasting Insulin | Insulin sensitivity was determined by assessment of fasting insulin. Fasting insulin increases with insulin resistance and tends to occur with NAFLD. | Baseline, Week 6, Week 12 | 
| Change in Fasting Glucose | Insulin sensitivity was determined by assessment of fasting glucose. The normal range for fasting glucose in children is 70-99 mg/dL. Diabetes mellitus is indicated with fasting glucose levels of 126 or greater. | Baseline, Week 6, Week 12 | 
| Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Score | The HOMA-IR score is calculated as fasting blood glucose level (nmol/L) multiplied by fasting insulin level (microU/L), divided by 22.5. Higher scores indicate increasing insulin resistance, although pediatric cut-points for HOMA-IR scores vary by gender and age. | Baseline, Week 6, Week 12 | 
| Absolute Change in Gamma-glutamyltransferase (GGT) | Gamma-glutamyl transferase (GGT) is a biomarker for NAFLD. Normal GGT values vary by age and the specific assay used. The normal range for males and females aged 11-18 is approximately 5-15 U/L. Increased GGT is associated with more severe NAFLD. | Baseline, Week 6, Week 12 | 
| Absolute Change in Total Cholesterol | Blood was drawn for a clinical lipid profile, including total cholesterol. Cholesterol is waxy substance which is produced by the liver or comes from food consumed. Cholesterol concentrations are commonly used as a marker for cardiovascular disease risk in adulthood Total cholesterol levels below 170 mg/100 milliliters (mL) of blood are in the normal range while levels at 200 and above are considered high. | Baseline, Week 6, Week 12 | 
| Absolute Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Blood was drawn for a clinical lipid profile, including total non-HDL-C. A measurement of non-HDL-C is obtained by subtracting high-density lipoprotein (HDL) level from total cholesterol. Non-HDL-C can predict atherosclerosis with as much accuracy as other lipoproteins can. Non-HDL-C values of 129 mg/dL or greater are considered high. | Baseline, Week 6, Week 12 | 
| Absolute Change in High-density Lipoprotein (HDL) Cholesterol | Blood was drawn for a clinical lipid profile, including total HDL cholesterol. HDL cholesterol is the good cholesterol because it is a type of fat that removes cholesterol from blood, thereby preventing build up. A healthy value for HDL cholesterol is 35 mg/dL and higher. Values under 35 mg/dL mean the child has a higher risk of developing heart disease. | Baseline, Week 6, Week 12 | 
| Absolute Change in Very-low-density Lipoprotein Cholesterol (VLDL-C) | Blood was drawn for a clinical lipid profile, including total VLDL cholesterol. VLDL cholesterol is produced in the liver and high levels are associated with increased plaque buildup in arteries. Values of VLDL-C that are 29 mg/dL or greater are considered high. | Baseline, Week 6, Week 12 | 
| Absolute Change in Low-density Lipoprotein (LDL) Cholesterol | Blood was drawn for a clinical lipid profile, including LDL cholesterol. LDL cholesterol levels below 110 mg/100 mL of blood are in the normal range while levels at 130 and above are considered high. | Baseline, Week 6, Week 12 | 
| Absolute Change in Triglycerides (TG) | Blood was drawn for a clinical lipid profile, including triglycerides. Triglycerides are made by the body and come from food consumed. High triglyceride levels increases the risk of heart disease and stroke. Triglyceride levels below 150 mg/dL are considered acceptable while levels greater than 200 mg/dL are considered high. | Baseline, Week 6, Week 12 | 
| Absolute Change in Apolipoprotein A-1 (ApoA-1) | Apolipoproteins transport lipids through the body by binding with fat and cholesterol to form lipoproteins. ApoA-1 is a component of HDL (good cholesterol) which transports cholesterol and phospholipids through the body to the liver. Among children aged 2 to 17 years, an ApoA-1 level of less than 115 mg/dL is considered low and levels greater than 120 mg/dL are considered acceptable. | Baseline, Week 6, Week 12 | 
| Absolute Change in Apolipoprotein B (ApoB) | Apolipoproteins transport lipids through the body by binding with fat and cholesterol to form lipoproteins. ApoB is a component of VLDL, intermediate-density lipoproteins (IDL), LDL, and chylomicrons. Among children aged 2 to 17 years, an ApoB level of less than 90 mg/dL is considered acceptable and levels of 100 mg/dL and greater are considered high. | Baseline, Week 6, Week 12 | 
| Absolute Change in Apolipoprotein C-II (ApoC-II) | Apolipoproteins transport lipids through the body by binding with fat and cholesterol to form lipoproteins. ApoC-II is a component of VLDL and chylomicrons. Normal values are between 3-5 mg/dL and abnormal values may be caused by a lipoprotein lipase deficiency resulting in fats not being broken down normally. Abnormal ApoC-II measurements may explain elevated levels of cholesterol and triglycerides. | Baseline, Week 6, Week 12 | 
| Absolute Change in Apolipoprotein E (ApoE) | Apolipoproteins transport lipids through the body by binding with fat and cholesterol to form lipoproteins. ApoE is a component of IDL and chylomicrons and carry cholesterol to the brain. Normal values of ApoE are between 3-7 mg/dL. Elevated ApoE may be associated with increased risk of dyslipidemia and atherosclerosis. | Baseline, Week 6, Week 12 | 
| Absolute Change in Apolipoprotein CIII (ApoCIII) | Apolipoproteins transport lipids through the body by binding with fat and cholesterol to form lipoproteins. ApoCIII is a component of VLDL, HDL, and triglyceride-rich chylomicrons and regulates lipid metabolism. Elevated ApoCIII is associated with atherosclerosis and cardiovascular disease. | Baseline, Week 6, Week 12 | 
| Absolute Change in High Sensitivity C-Reactive Protein (hsCRP) | High Sensitivity C-Reactive Protein (hsCRP) is a measurement assessing inflammation. Increased levels of hsCRP are associated with increased risk of cardiovascular disease or cardiovascular events such as stroke or heart attack. Values of hsCRP that are less than 1.0 mg/L are considered low risk, 1.0 to 3.0 mg/L indicates average risk, and values greater than 3.0 mg/L are considered high risk. | Baseline, Week 6, Week 12 | 
| Change in Interleukin 1 Beta (IL-1B) | Interleukin 1 beta is a cytokine protein involved in inflammatory response. A normal value for IL-1B is less than 3.9 picograms per milliliter (pg/mL). Increased IL-1B levels have been found to be associated with congestive heart failure. | Baseline, Week 6, Week 12 | 
| Change in Interleukin 6 (IL-6) | Interleukin 6 is a cytokine protein involved in the pro-inflammatory and anti-inflammatory response and stimulates an inflammatory response in many diseases, including atherosclerosis. Higher levels are generally interpreted as worsening of a disease condition. | Baseline, Week 6, Week 12 | 
| Change in Procollagen III | Procollagen III peptide levels can be used to assess the degree of collagen turnover and liver fibrosis. Increases in serum concentrations of procollagen III indicate a worsening disease state. | Baseline, Week 6, Week 12 | 
| Change in Particle Size of VLDL | Lipoprotein particle size will be assessed by Nuclear Magnetic Resonance (NMR). VLDL size ranges from 30-90 nanometers (nm) and is impacted by eating a meal high in fat. A linear relationship has been seen between VLDL particle size and NAFLD degree of severity. | Baseline, Week 6, Week 12 | 
| Change in Particle Size of HDL | Lipoprotein particle size will be assessed by Nuclear Magnetic Resonance (NMR). HDL size ranges from 7-13 nanometers (nm). Different sizes of HDL perform different functions in the body and this study will examine how HDL particle size is altered over time by the study treatment. | Baseline, Week 6, Week 12 | 
| Change in Particle Size of LDL | Lipoprotein particle size will be assessed by Nuclear Magnetic Resonance (NMR). LDL size ranges from 21-27 nanometers (nm) and is impacted by metabolic factors. This study will examine how LDL particle size is altered over time by the study treatment. | Baseline, Week 6, Week 12 | 
| Change in Particle Size of Chylomicrons | The size of chylomicrons in blood will be assessed throughout the study period. Chylomicrons are lipoprotein particles comprised of primarily of triglycerides and also contain phospholipids, and proteins. The size of chylomicrons varies and typically range from 75 to 600 nanometers (nm) in diameter. Chylomicrons are larger immediately following a meal. | Baseline, Week 6, Week 12 | 
| Change in Rate of de Novo Lipogenesis (DNL) | Rate of de novo lipogenesis (DNL) will be measured using stable isotope tracers. DNL is a biochemical process occurring in the liver where fatty acids are synthesized into carbohydrates. This study will examine how the rate of DNL is altered over time by the study treatment. | Baseline, Week 6, Week 12 | 
| Absolute Change in Abdominal Visceral Fat | Abdominal visceral fat was measured with the AMRA Medical body composition profile calculated from MRI images. | Baseline, Week 12 | 
| Absolute Change in Abdominal Subcutaneous Fat | Abdominal subcutaneous fat was measured with the AMRA Body composition profile calculated from MRI images. | Baseline, Week 12 | 
| Change in Liver Inflammation and Fibrosis (LIF) Score | LiverMultiScan by Perspectum Diagnostics is an imaging software tool that works with MRI providing a non-invasive way to diagnose liver disease. A LIF score of <1 represents a normal liver, 1-1.99 represents mild liver disease, 2-2.99 represents moderate liver disease, and a score ⩾3 represents severe liver disease. | Baseline, Week 12 | 
| Absolute Change in Height | Height in centimeters was measured at each study visit. | Baseline, Week 12 | 
| Absolute Change in Weight | Weight in kilograms was measured at each study visit. | Baseline, Week 12 | 
| Absolute Change in Body Mass Index (BMI) | Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters) squared (kg/m^2). The change in BMI between Baseline and Week 12 is presented here. | Baseline, Week 12 | 
| Absolute Change in Waist Circumference | Waist circumference was measured in centimeters at each study visit. The change is waist circumference between Baseline and Week 12 is presented here. | Baseline, Week 12 | 
| Pill Count | Adherence was assessed by pill counts of returned bottles. A total of 120 pills were dispensed for the 12 week study period. Taking one pill per day for 12 weeks means that 36 pills would be returned if the participant had perfect adherence. Pill counts greater than 36 mean that doses were skipped. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatrics, Lipids, Liver Diseases, Obesity