Study of Gemcabene in Adults With FPLD

Study Overview
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Brief Summary
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The overall objective of this study is to assess the efficacy and safety of two dosing regimens of gemcabene (300 mg once daily for 24 weeks or 300 mg daily for 12 weeks followed by 600 mg daily for 12 weeks) in up to eight patients with Familial Partial Lipodystrophy with high triglycerides and Non-Alcoholic Fatty Liver Disease. The study will consist of a six week Wash Out Period, up to a 28 day Screening Period, a 24 week Treatment Period, and a follow-on safety assessment four weeks post final dose. Study participation will last approximately 4 months and includes at least 9 study visits, and can be as many as 11 study visits.

Detailed Description
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Patients with typical Familial Partial Lipodystrophy Disease (FPLD) have a marked loss of subcutaneous fat from the extremities and trunk accompanied by a variable amount of excess fat deposition in the nonlipodystrophic areas such as the face, chin, back, and intraabdominal regions. Dietary fat restriction and other lifestyle changes are first line therapy to avoid weight gain, critical for effective management of metabolic complications in patients with lipodystrophy. However, despite lifestyle changes and conventional hypoglycemic and hypolipidemic therapies, some FPLD patients continue to have extreme hypertriglyceridemia, hepatic steatosis, and poorly controlled diabetes.Hypertriglyceridemia is a common condition of FPLD and serum triglyceride levels of 250-1999 mg/dL, classified as moderate to severe hypertriglyceridemia, indicate risk for development of very severe hypertriglyceridemia, causative of pancreatitis and hepatic steatosis. In patients such as those with FPLD with severe or very severe hypertriglyceridemia, fibrates, omega-3 fatty acids (OMG-3) and occasionally niacin are first-line therapy. Non-alcoholic fatty liver disease (NAFLD) is often associated with FPLD. The spectrum of NAFLD associated with FPLD which appears to be more frequent than what is seen in common Type 2 diabetes and appears more severe than common forms of NAFLD and very often associated with NASH. The etiology for the latter is not clear, however, the fact that a mouse model of liver specific laminopathy develops NASH in a cell -autonomous manner suggests that the specific cellular defects seen in FPLD may play a role in the development of NAFLD/NASH. Triglyceride content in the liver is regulated by fatty acid uptake as well as fatty acid and VLDL production rates. Derangements in these processes, such as excessive production of fatty acids and triglycerides that can occur with excessive carbohydrate consumption contribute to NAFLD. Patients with NAFLD compared to controls, present with an atherogenic dyslipidemic profile, characterized by increased serum levels of triglycerides, ApoB, VLDL-C, and LDL-C with a proportionally greater content of small dense LDL-C (sdLDL-C) 18-20. NAFLD is also associated with aberrant nuclear receptor function and systemic inflammation. NAFLD can progress to NASH. NASH is marked by hepatocyte ballooning and liver inflammation, which may progress to scarring and irreversible damage. Macro and microscopically, NASH is characterized by lobular and/or portal inflammation, varying degrees of fibrosis, hepatocyte death and pathological angiogenesis. At its most severe, NASH can progress to cirrhosis, hepatocellular carcinoma (HCC) and liver failure. It is estimated that 20-33% NAFLD patients will progress to NASH, with about 5% ultimately progressing to cirrhosis. Cirrhosis has a reported 7- to 10-year mortality of 12-25%. As NAFLD and NASH continue to be a growing epidemic, gemcabene's clinical and preclinical data suggest that this novel agent may provide benefit to patients with the diagnosis of NAFLD and/or NASH. As such, further development of gemcabene may help meet an unmet medical need in these patient populations. In Phase 2 studies, gemcabene has shown triglyceride lowering from 20 to > 50% based on dose and severity of hypertriglyceridemia and lowering in hsCRP of up to 50%. Additionally, in animal and cell based models, gemcabene studies have provided evidence demonstrating: reduction in de-novo lipogenesis, reduction in intrahepatic TG levels, modulation of inflammation and reduction of the NAFLD activity score, particularly related to hepatic ballooning, steatosis, fibrosis, and collagen accumulation. As such gemcabene may have utility in hypertriglyceridemia of FLP and ultimately in the prevention or treatment of NASH in these patients.

Official Title
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An Investigator-Initiated Open-Label, Randomized Study of Gemcabene in Adults With Familial Partial Lipodystrophy Disease (FPLD)

Conditions
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Familial Partial Lipodystrophy, Hypertriglyceridemia, Fatty Liver, NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: 300mg Gemcabene
* Drug: 600mg Gemcabene


Participation Criteria
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Eligibility Criteria
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Clinical diagnosis of lipodystrophy based on a lack of body fat in a partial fashion assessed by physical examination, and at least 1 MAJOR criterion (below): Low skinfold thickness in anterior thigh by caliper measurement: men (≤ 10 mm) and women (≤ 22 mm) OR Historic genetic diagnosis of familial partial lipodystrophy (e.g. mutations in LMNA, PPAR-γ, AKT2, or PLIN1 genes) as supported by source documentation Hepatic steatosis (>10% - Stage 2 or 3) as demonstrated by MRI-PDFF; Alcohol intake of less than 20 g per day in females and 30 g per day in males (one 12 oz beer, one glass of wine, or 2 oz of spirits or liquor equals roughly 10 g of alcohol; Mean fasting triglyceride value ≥ 250 mg/dL at the Screening Visit; Background lipid lowering medications must be stable for at least 6 weeks prior to the Screening Visit; Women patients must not be pregnant or lactating and women of child-bearing potential must agree to use acceptable methods of contraception throughout the duration of the study and for 30 days after the last dose of study drug. Male patients must agree to use contraception by means of a condom and may not donate sperm throughout the duration of the study and for 8 days after the last dose of study drug. Weight greater than 50 kg ( 110 lbs); with a body mass index (BMI) of no more than 45 kg/m²; Have not used a fibrate with in the last 6 weeks and/or thiazolidinediones (TZDs) within the last 12 weeks prior to the Screening visit. Do not have a hypersensitivity or a history of significant reactions of fibrates. Are not currently taking potent CYP3A4 inhibitors such as itraconazole or a macrolide antibiotic. Have a condition or finding which, in the opinion of the Investigator, would compromise the patient's safety or participation in the study.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 300 mg Gemcabene daily week 12-24<br>Patients took Gemcabene 300mg daily for weeks 1-12. After 12 weeks, at visit T4, patients were randomized 1:1 according to pre-generated randomization code. This arm received 300mg Gemcabene daily for 12 weeks total, starting at week 12. | Drug: 300mg Gemcabene<br>* 300mg Gemcabene<br>|
| Experimental: Group 2: 600mg Gemcabene daily week 12-24<br>Patients took Gemcabene 300mg daily for weeks 1-12. After 12 weeks, at visit T4, patients were randomized 1:1 according to pre-generated randomization code. This arm received 600mg Gemcabene daily for 12 weeks total, starting at week 12. | Drug: 600mg Gemcabene<br>* 600mg Gemcabene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Serum Triglyceride (at 12 Weeks) | This is measured by percent change in fasting serum triglyceride from baseline to week 12 | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Serum Triglycerides (Through 24 Weeks) | This is measured by change in fasting serum triglyceride from baseline to average of weeks 6 and 12, and week 24 and change in fasting serum triglyceride from baseline to week 12 | Baseline, week 6 and week 12, week 24 | 
| Percent Change in Fasting Serum Triglycerides (Through 24 Weeks) | This is measured by percent change in fasting serum triglyceride from baseline to average of weeks 6 and 12, and week 24 and change in fasting serum triglyceride from baseline to week 12 | Baseline, week 6 and week 12, week 24 | 
| Change in Liver Fat Content as Measured by Magnetic Resonance Imaging - Protein Density Fat Fraction (MRI-PDFF) | This is measured by change in liver fat content using Magnetic Resonance Imaging - Protein Density Fat Fraction (MRI-PDFF) from baseline to week 12 and week 24 | Baseline, week 12, week 24 | 
| Percent Change in Liver Fat Content as Measured by Magnetic Resonance Imaging - Protein Density Fat Fraction (MRI-PDFF) | This is measured by percent change in liver fat content using Magnetic Resonance Imaging - Protein Density Fat Fraction (MRI-PDFF) from baseline to week 12 and week 24 | Baseline, week 12, week 24 | 
| Change in Liver Fibrosis | This is measured by change in liver fibrosis using MR-elastography from baseline to week 12 and week 24 | Baseline, Week 12, and Week 24 | 
| Percent Change in Liver Fibrosis | This is measured by percent change in liver fibrosis using MR-elastography from baseline to week 12 and week 24 | Baseline, Week 12, and Week 24 | 
| Change in NAS (Non-alcoholic Steatohepatitis) | This is measured by change in NAS via non-alcoholic fatty liver disease activity score. NAS is the unweighted sum of steatosis, lobular inflammation and hepatocyte ballooning from baseline to week 24. Total NAS scores can range from 0 to 8. The higher the NAS score, the more severe the liver disease. | Baseline to week 24 | 
| Percent Change in NAS (Non-alcoholic Steatohepatitis) | This is measured by change in NAS via non-alcoholic fatty liver disease activity score. NAS is the unweighted sum of steatosis, lobular inflammation and hepatocyte ballooning from baseline to week 24. Total NAS scores can range from 0 to 8. The higher the NAS score, the more severe the liver disease. | Baseline to week 24 | 
| Change in Cholesterol | This will be measured by change in total, HDL and LDL levels in mg/dL | Baseline, week 6 and week 12, week 24 | 
| Percent Change in Cholesterol | This will be measured as percent change in total, HDL and LDL levels in mg/dL. | Baseline, week 6 and week 12, week 24 | 
| Change in Apolipoprotein | This will be measured by change in apolipoprotein A and B in mg/dL | Baseline, week 6 and week 12, week 24 | 
| Percent Change in Apolipoprotein | This will be measured by percent change in apolipoprotein A and B in mg/dL | Baseline, week 6 and week 12, week 24 | 
| Change in High-Sensitivity C-Reactive Protein (hsCRP) | This is measured by change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 12 and week 24 | Baseline, week 12, week 24 | 
| Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) | This is measured by percent change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 12 and week 24 | Baseline, week 12, week 24 | 
| Change in Alanine Aminotransferase (ALT) | This is measured by change in alanine aminotransferase (ALT) from baseline to weeks 12 and week 24 | Baseline, week 12, week 24 | 
| Percent Change in Alanine Aminotransferase (ALT) | This is measured by percent change in alanine aminotransferase (ALT) from baseline to weeks 12 and week 24 | Baseline, week 12, week 24 | 
| Change in Aspartate Aminotransferase (AST) | This is measured by change in aspartate aminotransferase (AST) from baseline to weeks 12 and week 24 | Baseline, week 12, week 24 | 
| Percent Change in Aspartate Aminotransferase (AST) | This is measured by percent change in aspartate aminotransferase (AST) from baseline to weeks 12 and week 24 | Baseline, week 12, week 24 |