A Randomized, Double Blind, Placebo-Controlled Study to Assess Efficacy, Safety and Tolerability of ISIS 304801 in Patients With Partial Lipodystrophy With an Open-Label Extension
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Lipodystrophy
- Sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Enrollment
- 5
- Locations
- 1
- Primary Endpoint
- Change in Log 10 Fasting Triglycerides.
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
Background:
Partial lipodystrophy is a deficiency of body fat in parts of the body (usually the arms and legs). People with partial lipodystrophy often get high blood triglyceride (fat) level, insulin resistance, diabetes and other problems. Researchers think the new drug ISIS 304801 can help treat health problems caused by partial lipodystrophy.
Objective:
To see if ISIS 304801 will improve blood fat (triglyceride levels), diabetes, and liver disease, and reduce some risks for heart disease caused by partial lipodystrophy.
Eligibility:
Adults at least 18 years old with partial lipodystrophy.
Design:
Participants will be screened during a 1-week stay at NIH. They will have:
Blood and urine tests
Physical exam.
Assignment to get either the study drug or placebo.
Instructions for how to inject the drug.
Body measurements.
Heart tests.
Participants will give themselves injections of the drug or placebo once a week at home. Some may test blood sugar by finger pricks. They will have monthly phone calls and nurse visits to take blood tests.
After 4 months, participants may continue the study for 1 year. All participants will get the study drug.
Participants will have study visits at NIH every 4 months. These may include:
Insulin sensitivity measurement: Insulin and sugar will be infused through 2 intravenous (IV) lines in the arms. Blood will be drawn.
Sugar and fat metabolism measured by IV infusions and blood tests.
Special x-ray scan to measure body fat.
Liquid meal then blood collected by IV catheter in the arm.
Magnetic resonance imaging scans.
Neck ultrasound.
Questionnaires.
Liver biopsy (optional)
Injection of heparin (a blood thinner) before a blood test.
After finishing the drug, participants will have 1 nurse visit and 1 visit to NIH.
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Detailed Description
Background: Lipodystrophy is a rare disease of deficient adipose mass, characterized by severe hypertriglyceridemia as well as insulin resistance, diabetes mellitus, fatty liver disease, acute pancreatitis, and early cardiovascular events. Apolipoprotein C-III (apoC-III) regulates triglyceride metabolism, and apoC-III levels strongly correlate with serum triglycerides in a variety of patient populations. Patients with genetically low levels of apoC-III have lower triglycerides and reduced cardiovascular disease, while individuals with genetically elevated levels of apoC-III have higher triglycerides and increased non-alcoholic fatty liver disease and insulin resistance. Pharmacologic reduction of apoC-III using anti-sense oligonucleotides (ASOs) reduce triglycerides by \~60-70% in a tested patient populations. Aim: The purpose of this study is to determine if apoC-III reduction using an ASO to apoC-III (ISIS 304801) will reduce triglycerides and improve insulin resistance, diabetes, and hepatic steatosis in patients with lipodystrophy. The primary hypothesis to be tested is: 1. ISIS 304801will reduce log10 fasting serum triglycerides. Secondary and tertiary hypotheses to be tested are: 2. ISIS 304801will improve glucose metabolism by improving insulin resistance. 3. ISIS 304801 will reduce hepatic steatosis. 4. ISIS 304801 will improve cardiovascular risk markers. We will also explore the mechanism of action of apoC-III ASO by studying lipoprotein lipase activity and lipoprotein particle distribution. Methods: This study will enroll up to 20 patients with partial lipodystrophy with a goal of 10 study completers. The study will be conducted in two phases. The first is a 16-week, randomized, double-blind, placebo-controlled design. Subjects will be treated with ISIS 304801 at a target dose of 300 mg per week or placebo. Following this phase, all subjects will enter a 12 month open-label extension in which they will receive active drug. Patients who experience benefit (triglyceride lowering greater than or equal to 50%) may receive an additional 12 months of open-label drug (up to 24 months, total). Measurement of the primary outcome (serum triglycerides) and key secondary outcomes will be performed at baseline prior to the intervention, after 13 weeks (primary outcome only) or 16 weeks (primary and secondary outcomes) of blinded drug or placebo, and after an additional 4 months of active drug in subjects initially randomized to placebo.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Placebo
Placebo administered subcutaneously (SC)
Intervention: Placebo
ISIS 304801
300 mg of study drug administered via SC
Intervention: ISIS 304801
Outcomes
Primary Outcomes
Change in Log 10 Fasting Triglycerides.
Time Frame: Baseline and 16 weeks
Change from baseline to 16 weeks in log 10 fasting triglycerides
Secondary Outcomes
- Change in HbA1c(Baseline and 16 weeks)
- Plasma ISIS 304801 Level(16 weeks)
- Change in Lipolysis Rate (Palmitate)(Baseline and 16 weeks)
- Change From Baseline in Liver Volume(Baseline and 16 weeks)
- Change in Lipolysis Rate (Glycerol)(Baseline and 16 weeks)
- Change From Baseline in Hepatic Steatosis(Baseline and 16 weeks)
- Change in Fasting Plasma Glucose(Baseline and 16 weeks)
- Change in Lipoprotein Lipase Activity(Baseline and 16 weeks)
- Change in Total Body Insulin Sensitivity(Baseline and 16 weeks)