Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension

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. ...

Timeline

Start

2015-12-23

Primary completion

2019-09-26

Completion

2019-09-26

Publications

• Background Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014 Jul 3;371(1):32-41. doi: 10.1056/NEJMoa1308027. Epub 2014 Jun 18.
• Background Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, Singleton W, Viney N, Geary R, Su J, Baker BF, Burkey J, Crooke ST, Crooke RM. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013 May 24;112(11):1479-90. doi: 10.1161/CIRCRESAHA.111.300367. Epub 2013 Mar 29.
• Background Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, Geary RS, Hughes SG, Viney NJ, Graham MJ, Crooke RM, Witztum JL, Brunzell JD, Kastelein JJ. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015 Jul 30;373(5):438-47. doi: 10.1056/NEJMoa1400283.
• Background Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014 Dec 4;371(23):2200-6. doi: 10.1056/NEJMoa1400284.
• Lightbourne M, Startzell M, Bruce KD, Brite B, Muniyappa R, Skarulis M, Shamburek R, Gharib AM, Ouwerkerk R, Walter M, Eckel RH, Brown RJ. Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy. J Clin Lipidol. 2022 Nov-Dec;16(6):850-862. doi: 10.1016/j.jacl.2022.06.011. Epub 2022 Sep 22.

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