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Study of Gemcabene in Adults With FPLD

Primary Purpose

Familial Partial Lipodystrophy, Hypertriglyceridemia, Fatty Liver

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
300mg Gemcabene
600mg Gemcabene
Sponsored by
Elif Oral
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Partial Lipodystrophy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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.

Sites / Locations

  • University of Michigan

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group 1: 300 mg Gemcabene daily week 12-24

Group 2: 600mg Gemcabene daily week 12-24

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change in Fasting Serum Triglyceride (at 12 Weeks)
This is measured by percent change in fasting serum triglyceride from baseline to week 12

Secondary Outcome Measures

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
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
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
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
Change in Liver Fibrosis
This is measured by change in liver fibrosis using MR-elastography from baseline to 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
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.
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.
Change in Cholesterol
This will be measured by change in total, HDL and LDL levels in mg/dL
Percent Change in Cholesterol
This will be measured as percent change in total, HDL and LDL levels in mg/dL.
Change in Apolipoprotein
This will be measured by change in apolipoprotein A and B in mg/dL
Percent Change in Apolipoprotein
This will be measured by percent change in apolipoprotein A and B in mg/dL
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
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
Change in Alanine Aminotransferase (ALT)
This is measured by change in alanine aminotransferase (ALT) from baseline to weeks 12 and 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
Change in Aspartate Aminotransferase (AST)
This is measured by change in aspartate aminotransferase (AST) from baseline to weeks 12 and 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

Full Information

First Posted
April 3, 2018
Last Updated
July 31, 2020
Sponsor
Elif Oral
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1. Study Identification

Unique Protocol Identification Number
NCT03508687
Brief Title
Study of Gemcabene in Adults With FPLD
Official Title
An Investigator-Initiated Open-Label, Randomized Study of Gemcabene in Adults With Familial Partial Lipodystrophy Disease (FPLD)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
March 13, 2018 (Actual)
Primary Completion Date
July 31, 2019 (Actual)
Study Completion Date
July 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Elif Oral

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Partial Lipodystrophy, Hypertriglyceridemia, Fatty Liver, NASH - Nonalcoholic Steatohepatitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1: 300 mg Gemcabene daily week 12-24
Arm Type
Experimental
Arm Description
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.
Arm Title
Group 2: 600mg Gemcabene daily week 12-24
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
300mg Gemcabene
Intervention Description
300mg Gemcabene
Intervention Type
Drug
Intervention Name(s)
600mg Gemcabene
Intervention Description
600mg Gemcabene
Primary Outcome Measure Information:
Title
Change in Fasting Serum Triglyceride (at 12 Weeks)
Description
This is measured by percent change in fasting serum triglyceride from baseline to week 12
Time Frame
Baseline to week 12
Secondary Outcome Measure Information:
Title
Change in Fasting Serum Triglycerides (Through 24 Weeks)
Description
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
Time Frame
Baseline, week 6 and week 12, week 24
Title
Percent Change in Fasting Serum Triglycerides (Through 24 Weeks)
Description
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
Time Frame
Baseline, week 6 and week 12, week 24
Title
Change in Liver Fat Content as Measured by Magnetic Resonance Imaging - Protein Density Fat Fraction (MRI-PDFF)
Description
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
Time Frame
Baseline, week 12, week 24
Title
Percent Change in Liver Fat Content as Measured by Magnetic Resonance Imaging - Protein Density Fat Fraction (MRI-PDFF)
Description
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
Time Frame
Baseline, week 12, week 24
Title
Change in Liver Fibrosis
Description
This is measured by change in liver fibrosis using MR-elastography from baseline to week 12 and week 24
Time Frame
Baseline, Week 12, and Week 24
Title
Percent Change in Liver Fibrosis
Description
This is measured by percent change in liver fibrosis using MR-elastography from baseline to week 12 and week 24
Time Frame
Baseline, Week 12, and Week 24
Title
Change in NAS (Non-alcoholic Steatohepatitis)
Description
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.
Time Frame
Baseline to week 24
Title
Percent Change in NAS (Non-alcoholic Steatohepatitis)
Description
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.
Time Frame
Baseline to week 24
Title
Change in Cholesterol
Description
This will be measured by change in total, HDL and LDL levels in mg/dL
Time Frame
Baseline, week 6 and week 12, week 24
Title
Percent Change in Cholesterol
Description
This will be measured as percent change in total, HDL and LDL levels in mg/dL.
Time Frame
Baseline, week 6 and week 12, week 24
Title
Change in Apolipoprotein
Description
This will be measured by change in apolipoprotein A and B in mg/dL
Time Frame
Baseline, week 6 and week 12, week 24
Title
Percent Change in Apolipoprotein
Description
This will be measured by percent change in apolipoprotein A and B in mg/dL
Time Frame
Baseline, week 6 and week 12, week 24
Title
Change in High-Sensitivity C-Reactive Protein (hsCRP)
Description
This is measured by change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 12 and week 24
Time Frame
Baseline, week 12, week 24
Title
Percent Change in High-Sensitivity C-Reactive Protein (hsCRP)
Description
This is measured by percent change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 12 and week 24
Time Frame
Baseline, week 12, week 24
Title
Change in Alanine Aminotransferase (ALT)
Description
This is measured by change in alanine aminotransferase (ALT) from baseline to weeks 12 and week 24
Time Frame
Baseline, week 12, week 24
Title
Percent Change in Alanine Aminotransferase (ALT)
Description
This is measured by percent change in alanine aminotransferase (ALT) from baseline to weeks 12 and week 24
Time Frame
Baseline, week 12, week 24
Title
Change in Aspartate Aminotransferase (AST)
Description
This is measured by change in aspartate aminotransferase (AST) from baseline to weeks 12 and week 24
Time Frame
Baseline, week 12, week 24
Title
Percent Change in Aspartate Aminotransferase (AST)
Description
This is measured by percent change in aspartate aminotransferase (AST) from baseline to weeks 12 and week 24
Time Frame
Baseline, week 12, week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elif A Oral, M.D.
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48105
Country
United States

12. IPD Sharing Statement

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Study of Gemcabene in Adults With FPLD

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