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Gemcabene for the Treatment of Pediatric NAFLD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03436420
Recruitment Status : Active, not recruiting
First Posted : February 16, 2018
Last Update Posted : November 7, 2018
Sponsor:
Collaborator:
Gemphire Therapeutics, Inc.
Information provided by (Responsible Party):
Miriam Vos, MD, Emory University

Brief 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 ALT, hepatic steatosis, dyslipidemia and down regulate de novo lipogenesis in children with NAFLD.

Condition or disease Intervention/treatment Phase
Non-Alcoholic Fatty Liver Disease Drug: Gemcabene Phase 2

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 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gemcabene for the Treatment of Pediatric NAFLD: A Phase 2a Study
Actual Study Start Date : March 29, 2018
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2019


Arm Intervention/treatment
Experimental: Gemcabene
Children receiving 12 weeks of treatment with gemcabene
Drug: Gemcabene
Participants will take 300 milligrams (mg) of gemcabene, once per day for 12 weeks.
Other Name: Gemcabene calcium




Primary Outcome Measures :
  1. Percent change in alanine aminotransferase (ALT) [ Time Frame: Baseline, Week 12 ]
    Percent change in alanine aminotransferase (ALT) from baseline to 12 weeks will be 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.


Secondary Outcome Measures :
  1. Absolute change in ALT [ Time Frame: Baseline, Week 6, Week 12 ]
    Absolute change in ALT among study participants will be reported. 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.

  2. Percent change in ALT between study visits [ Time Frame: Baseline, Week 6, Week 12 ]
    Percent change in ALT from baseline to week 6 and the mean of week 6 and week 12 will be 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.

  3. Change in hepatic steatosis [ Time Frame: Baseline, Week 12 ]
    Change in hepatic steatosis (fat accumulation in the liver) will be 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.

  4. Change in aspartate aminotransferase (AST) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  5. Change in Liver Inflammation and Fibrosis (LIF) score [ Time Frame: Baseline, Week 12 ]
    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.

  6. Change in abdominal visceral fat and abdominal subcutaneous fat [ Time Frame: Baseline through week 12 ]
    AMRA Body composition profile calculated from MRI images

  7. Change in insulin sensitivity [ Time Frame: Baseline, Week 6, Week 12 ]
    Insulin sensitivity will be determined by assessment of fasting insulin, fasting glucose, and homeostatic model assessment of insulin resistance (HOMA-IR). Participants will be designated as having insulin sensitivity or not having insulin sensitivity based on lab values.

  8. Change in Gamma-glutamyltransferase (GGT) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  9. Change in total cholesterol [ Time Frame: Baseline, Week 6, Week 12 ]
    Blood will be 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.

  10. Change in Apolipoprotein B (ApoB) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  11. Change in non-high-density lipoprotein cholesterol (non-HDL-C) [ Time Frame: Baseline, Week 6, Week 12 ]
    Blood will be 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.

  12. Change in high-density lipoprotein (HDL) cholesterol [ Time Frame: Baseline, Week 6, Week 12 ]
    Blood will be 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.

  13. Change in very-low-density lipoprotein cholesterol (VLDL-C) [ Time Frame: Baseline, Week 6, Week 12 ]
    Blood will be 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.

  14. Change in low-density lipoprotein (LDL) cholesterol [ Time Frame: Baseline, Week 6, Week 12 ]
    Blood will be 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.

  15. Change in triglycerides (TG) [ Time Frame: Baseline, Week 6, Week 12 ]
    Blood will be 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.

  16. Change in apolipoprotein A-1 (ApoA-1) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  17. Change in Apolipoprotein C-II (ApoC-II) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  18. Change in Apolipoprotein E (ApoE) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  19. Change in particle size of VLDL [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  20. Change in Apolipoprotein CIII (ApoCIII) [ Time Frame: Baseline, Week 6, Week 12 ]
    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. Normal values of ApoE are approximately 8-15 mg/dL. Elevated ApoCIII is associated with atherosclerosis and cardiovascular disease.

  21. Change in High Sensitivity C-Reactive Protein (hsCRP) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  22. Change in interleukin 1 beta (IL-1B) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  23. Change in Interleukin 6 (IL-6) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  24. Change in procollagen III [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  25. Change in particle size of HDL [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  26. Change in particle size of LDL [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  27. Change in particle size of chylomicrons [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  28. Change in rate of de novo lipogenesis (DNL) [ Time Frame: Baseline, Week 6, Week 12 ]
    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.

  29. Change in height [ Time Frame: Baseline through Week 12 ]
    Height in centimeters will be measured at each study visit.

  30. Change in weight [ Time Frame: Baseline through Week 12 ]
    Weight in kilograms will be measured at each study visit.

  31. Change in body mass index (BMI) [ Time Frame: Baseline through Week 12 ]
    Body mass index (BMI) will be calculated as weight (kg) / [height (m)]2

  32. Change in waist circumference [ Time Frame: Baseline through Week 12 ]
    Waist circumference will be measured in centimeters at each study visit.

  33. Pill count [ Time Frame: Week 12 ]
    Adherence will be assessed by pill counts of returned bottles.

  34. Number of participants completing the study [ Time Frame: Week 12 ]
    Compliance will be measured by the number of participants who complete the study.



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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/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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03436420


Locations
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United States, Georgia
Children's Healthcare of Atlanta / Emory University
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Gemphire Therapeutics, Inc.
Investigators
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Principal Investigator: Miriam B Vos, MD Emory University

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Responsible Party: Miriam Vos, MD, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT03436420     History of Changes
Other Study ID Numbers: IRB00099844
First Posted: February 16, 2018    Key Record Dates
Last Update Posted: November 7, 2018
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Miriam Vos, MD, Emory University:
Pediatrics
Lipids
Liver Diseases
Obesity

Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases