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

NCT02639286 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 16003816-DK-0038
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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. ...

Conditions

Lipodystrophy

Keywords

Lipodystrophy; Hypertriglyceridemia

Outcome Measures

Primary Outcomes (1)

• Change in Log 10 Fasting Triglycerides.

  Change from baseline to 16 weeks in log 10 fasting triglycerides

  Baseline and 16 weeks

Secondary Outcomes (9)

• Change in Lipolysis Rate (Glycerol)

  Baseline and 16 weeks

• Change in Lipolysis Rate (Palmitate)

  Baseline and 16 weeks

• Change From Baseline in Liver Volume

  Baseline and 16 weeks

• Change From Baseline in Hepatic Steatosis

  Baseline and 16 weeks

• Change in Lipoprotein Lipase Activity

  Baseline and 16 weeks

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo administered subcutaneously (SC)

Drug: Placebo

ISIS 304801

EXPERIMENTAL

300 mg of study drug administered via SC

Drug: ISIS 304801

Interventions

ISIS 304801 DRUG

300 mg of ISIS 304801 administered as SC

ISIS 304801

Placebo DRUG

Placebo administered via SC

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to 18 years at enrollment (the time of informed consent, week -1)
• Fasting triglyceride (TG) levels greater than or equal to 500 mg/dL (greater than or equal to 5.7 mmol/L) at enrollment. If the fasting TG value is \<500 mg/dL (\<5.7 mmol/L) but greater than or equal to 350 mg/dL (greater than or equal to 4.0 mmol/L) up to two additional tests may be performed in order to qualify, and a single level greater than or equal to 500 mg/dL will permit enrollment.
• Fasting TG levels greater than or equal to 200 mg/DL (2.6 mmol/L) with a hemoglobin A1C over 7%.
• Willing to maintain their customary physical activity level and to follow a diet moderate in carbohydrates and fats with a focus on complex carbohydrates and replacing saturated for unsaturated fats
• Clinical diagnosis of lipodystrophy based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination, and low skinfold thickness in anterior thigh by caliper measurement: men (less than or equal to 10mm) and women (less than or equal to 22mm), plus one of the following:
• Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPARG, AKT2, or PLIN1 genes) OR
• Family history of familial PL or abnormal and similar fat distribution plus 1 minor criterion (below), OR
• minor criteria (below) in the absence of genetic diagnosis of family history
• MINOR Criteria
• Diabetes mellitus with requirement for high doses of insulin, eg, requiring greater than or equal to 200 U/day,greater than or equal to 2 U/kg/day, or currently taking U-500 insulin
• Presence of acanthosis nigricans on physical examination
• History of polycystic ovary syndrome (PCOS) or PCOS-like symptoms (hirsutism, oligomenorrhea, and/or polycystic ovaries)
• History of pancreatitis associated with hypertriglyceridemia
• Evidence of non-alcoholic fatty liver disease: Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease or Radiographic evidence of hepatic steatosis (e.g., on ultrasound or CT)
• Satisfy one of the following:

You may not qualify if:

• A diagnosis of generalized lipodystrophy
• Current or history of autoimmune diseases (even with a diagnosis of PL) unless approved by the Investigator and Sponsor Medical Monitor
• Acute pancreatitis within 4 weeks of enrollment
• History within 6 months of enrollment of acute or unstable cardiac ischemia (myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack, or unstable congestive heart failure requiring a change in medication
• Major surgery within 3 months of enrollment
• History of heart failure with New York Heart Association functional classification (NYHA) greater than Class II
• Uncontrolled hypertension (blood pressure \[BP\] \>160/100 mm Hg)
• Any of the following laboratory values at enrollment:
• Cardiac troponin T \> upper limit of normal (ULN)
• Measured or estimated (in case of triglycerides \> 400 mg/dL) LDL-C \>130 mg/dL on maximal tolerated statin therapy
• Hemoglobin HbA1c greater than or equal to 9.5%
• Hepatic:
• Total bilirubin \>ULN
• Alanine transaminase (ALT) \>3.0 x ULN. Higher levels will be permitted after a safety review by a hepatologist, that includes no evidence of cirrhosis.
• Aspartate aminotransferase ( (AST) \>3.0 x ULN. Higher levels will be permitted after a safety review by a hepatologist, that includes no evidence of cirrhosis.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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.

  PMID: 24941082 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.

  PMID: 23542898 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.

  PMID: 26222559 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.

  PMID: 25470695 BACKGROUND

• 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.

  PMID: 36195542 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lipodystrophy; Hypertriglyceridemia

Interventions

ISIS 304801

Condition Hierarchy (Ancestors)

Skin Diseases, Metabolic; Skin Diseases; Skin and Connective Tissue Diseases; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperlipidemias; Dyslipidemias

Results Point of Contact

• Title: Dr. Rebecca Brown
• Organization: NIDDK

rebecca.brown@nih.gov

301-594-0609

Study Officials

• Rebecca J Brown, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 23, 2015
• First Posted: December 24, 2015
• Study Start: December 23, 2015
• Primary Completion: September 26, 2019
• Study Completion: September 26, 2019
• Last Updated: October 20, 2020
• Results First Posted: October 20, 2020

Record last verified: 2020-01-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)