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LipodystrophyPhase 2NCT02639286

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

A Phase 2 study testing ISIS 304801 in people with Lipodystrophy, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Lipodystrophy
What is being tested?
ISIS 304801
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
5 participants
Where
1 siteUnited States
Study dates
23 Dec 2015to 26 Sep 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • OR
  • 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:
Show all 19Show fewer
  • 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
  • 2 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:
  • Females: Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal (defined as 12 months of spontaneous amenorrhea in females >55 years of age or, in females less than or equal to 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved), abstinent, or if engaged in sexual relations of child-bearing potential, patient is using an acceptable contraceptive method from time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug administration.
  • Males: Surgically sterile, abstinent, or if engaged in sexual relations with a female of child bearing potential, patient is utilizing an acceptable contraceptive method from the time of signing the informed consent form until at least 13 weeks after the last dose of study drug administration.
  • Note: Abstinence is only an effective method of birth control when this is the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception.

Who cannot join

  • 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
Show all 43Show fewer
  • 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.
  • Renal:
  • Persistently positive (2 out of 3 tests greater than or equal to trace positive) for blood on urine dipstick. In the event of a positive test eligibility may be confirmed with urine microscopy showing less than or equal to 5 red blood cells per high power field (urine will be screened at admission and repeated if abnormal). If red blood cell counts (RBC) are high every effort will be made to determine if the source is renal or benign, such as from menstrual bleeding. If the presence of RBC is determined to be from a non-renal source, the PI will make the decision to proceed with protocol testing and/or randomization.
  • Two out of three consecutive tests greater than or equal to 1+ for protein on urine dipstick. In the event of a positive test eligibility may be confirmed by either a spot urine albumin to creatinine ratio <1000mg/g or a quantitative total urine albumin measurement of < 1g/24 hrs (urine will be screened at admission and repeated if abnormal)
  • Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault <60 mL/min
  • Platelet count below 140,000 K/uL
  • Clinically significant (as determined by the Investigator or Sponsor) abnormalities on laboratory examination that will increase risk to the patient or interfere with data integrity
  • Uncontrolled hypothyroidism (abnormal thyroid function tests should be approved by the Investigator)
  • History within 6 months of enrollment of screening of drug or alcohol abuse
  • History of bleeding diathesis or coagulopathy or clinically significant abnormality in coagulation parameters at enrollment
  • Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to enrollment
  • Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
  • Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
  • Treatment with another investigational drug, biological agent, or device within one month of enrollment, or 5 half-lives of investigational agent, whichever is longer
  • Unwilling to comply with contraceptive and lifestyle (diet/exercise) requirements
  • Use of any of the following:
  • Use of metreleptin within the last 3 months prior to enrollment
  • Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a stable dose for at least 3 months prior to enrollment
  • Insulin unless on a stable daily insulin dose regimen (+/- 20 %) for at least 4 weeks prior to enrollment
  • Use of nicotinic acid or derivatives within the last 4 weeks prior to enrollment
  • Systemic corticosteroids or anabolic steroids within 6 weeks prior to enrollment unless approved by the Investigator
  • Antihypertensive medication unless on a stable dose for at least 4 weeks prior to enrollment
  • Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to enrollment and dose and regimen expected to remain constant throughout the study
  • Oral anticoagulants unless on a stable dose for at least 4 weeks prior to enrollment and regular clinical monitoring is performed
  • Prior exposure to ISIS 304801
  • Anti-obesity drugs [e.g., the combination of phentermine and extended-release topiramate (Osymia, orlistat (Xenical), liraglutide [rDNA origin] injection (Saxenda) and lorcaserin (Belvig), phentermine, amphetamines, herbal preparations] within 12 weeks prior to screening
  • Any other medication unless stable at least 4 weeks prior to enrollment (occasional or intermittent use of over-the-counter medications will be allowed at Investigator s discretion)
  • Blood donation of 50 to 499 mL within 30 days or of >499 mL within 60 days
  • Have any other conditions, which, in the opinion of the Investigator or the Sponsor would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: 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

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.

Read more

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.

...

Read the 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.

Conditions
Lipodystrophy
Being tested
ISIS 304801, Placebo
Keywords
Lipodystrophy, Hypertriglyceridemia
Medical subject headings
Lipodystrophy, Hypertriglyceridemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ISIS 304801Drug

    300 mg of ISIS 304801 administered as SC

  • PlaceboDrug

    Placebo administered via SC

Study groups in NCT02639286
Study groupRoleWhat they receive
PlaceboPlacebo comparatorPlacebo administered subcutaneously (SC)
Receives: Drug: Placebo
ISIS 304801Experimental300 mg of study drug administered via SC
Receives: Drug: ISIS 304801

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Log 10 Fasting Triglycerides.

    Change from baseline to 16 weeks in log 10 fasting triglycerides

    Measured: Baseline and 16 weeks

Secondary outcomes (9)

  1. Change in Lipolysis Rate (Glycerol)

    Change in lipolysis rate measured using stable isotope tracers (Glycerol rate of appearance) (mg/kgLBM/min)

    Measured: Baseline and 16 weeks

  2. Change in Lipolysis Rate (Palmitate)

    Change in lipolysis rate measured using stable isotope tracers (Palmitate rate of appearance) measured in milligrams per kilogram lean body mass per minute (mg/kgLBM/min)

    Measured: Baseline and 16 weeks

  3. Change From Baseline in Liver Volume

    Change from baseline in hepatic steatosis (magnetic resonance spectroscopy) (mL)

    Measured: Baseline and 16 weeks

  4. Change From Baseline in Hepatic Steatosis

    Change from baseline in hepatic steatosis via magnetic resonance spectroscopy

    Measured: Baseline and 16 weeks

  5. Change in Lipoprotein Lipase Activity

    Lipoprotein lipase activity in plasma is measured using blood samples obtained 10 minutes after intravenous infusion of 60 units/kg of unfractionated heparin.

    Measured: Baseline and 16 weeks

  6. Change in Total Body Insulin Sensitivity

    Change in total body insulin sensitivity using the hyperinsulinemic euglycemic clamp (mg/kgLBM/min)

    Measured: Baseline and 16 weeks

  7. Change in HbA1c

    Change in hemoglobin A1c (HbA1c) (%)

    Measured: Baseline and 16 weeks

  8. Change in Fasting Plasma Glucose

    Change in fasting plasma glucose in mg/dL

    Measured: Baseline and 16 weeks

  9. Plasma ISIS 304801 Level

    Measured via a non-compartmental plasma PK analysis of ISIS 304801

    Measured: 16 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Dec 2015 (estimated)
  2. Study start23 Dec 2015
  3. Primary completion26 Sep 2019
  4. Study completion26 Sep 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02639286
Sponsor's protocol ID
160038
Other IDs
16-DK-0038
Status last verified
3 Jan 2020
First submitted
23 Dec 2015
Last updated
20 Oct 2020
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Data will not be shared due to the small number of participants

Publications

  • 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.

    PubMed 24941082

  • 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.

    PubMed 23542898

  • 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.

    PubMed 26222559

  • 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.

    PubMed 25470695

  • 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.

    PubMed 36195542

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ISIS 304801 in people with Lipodystrophy, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 43 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Log 10 Fasting Triglycerides. (time frame: Baseline and 16 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02639286, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2020.

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