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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS ANGPTL3-LRx in Healthy Volunteers With Elevated Triglycerides and Subjects With Familial Hypercholesterolemia

This study is currently recruiting participants.
Verified May 2017 by Ionis Pharmaceuticals, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02709850
First Posted: March 16, 2016
Last Update Posted: May 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Akcea Therapeutics
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.
  Purpose
The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS ANGPTL3-LRx (ISIS 703802) given to healthy volunteer subjects with elevated triglycerides and subjects with familial hypercholesterolemia.

Condition Intervention Phase
Hypertriglyceridemia Familial Hypercholesterolemia Drug: IONIS ANGPTL3-LRx Drug: Placebo (0.9%NaCl, water, riboflavin) Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
Official Title: A Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of ISIS 703802, Targeting ANGPTL3, Administered Subcutaneously to Healthy Volunteers With Elevated Triglycerides and Subjects With Familial Hypercholesterolemia

Resource links provided by NLM:


Further study details as provided by Ionis Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Safety and tolerability of single and multiple doses of IONIS ANGPTL3-LRx (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters) [ Time Frame: Up to Day 127 ]
    The safety and tolerability of IONIS ANGPTL3-LRx will be assessed by determining the incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters by dose. Safety results in subjects dosed with IONIS ANGPTL3-LRx will be compared with those from subjects dosed with placebo.

  • Pharmacokinetics after single and multiple doses of IONIS ANGPTL3-LRx. [ Time Frame: Up to Day 127 ]
    The plasma pharmacokinetics (concentration-time results) of IONIS ANGPTL3-LRx (unconjugated and conjugated ASO) will be assessed following single and multiple-dose SC administration. The amount of IONIS ANGPTL3-LRx excreted in urine at selected 24-hour intervals will also be determined.

  • Pharmacodynamics of IONIS ANGPTL3-LRx (Changes in serum ANGPTL3 levels) [ Time Frame: Up to Day 127 ]
    Changes in serum angiopoietin-like 3 (ANGPTL3) levels compared to baseline.


Secondary Outcome Measures:
  • Pharmacodynamic effects of IONIS ANGPTL3-LRx [ Time Frame: Up to Day 127 ]
    Effects of IONIS ANGPTL3-LRx on changes in ANGPTL3 plasma protein compared to baseline.


Estimated Enrollment: 61
Study Start Date: November 2015
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohorts A to D
Single dose by subcutaneous (SC) injection
Drug: IONIS ANGPTL3-LRx Drug: Placebo (0.9%NaCl, water, riboflavin)
Experimental: Cohort EE
Multiple doses by subcutaneous (SC) injection
Drug: IONIS ANGPTL3-LRx
Experimental: Cohort AA to DD, and FF
Multiple doses by subcutaneous (SC) injection
Drug: IONIS ANGPTL3-LRx Drug: Placebo (0.9%NaCl, water, riboflavin)

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria for All Cohorts:

  • Must have given written informed consent and be able to comply with all study requirements
  • Males or females 18 to 65 years, inclusive, at the time of informed consent
  • BMI ≤ 35.0 kg/m2
  • Females must be non-pregnant and non-lactating, and either surgically sterile or postmenopausal.
  • Males must be surgically sterile, abstinent or using an acceptable contraceptive method

Inclusion criteria for Cohorts, A, D, and AA to DD only:

  • Fasting TG ≥ 150 mg/dL at Screening
  • Fasting LDL-C > 70 mg/dL at Screening

Inclusion criteria for Cohorts B and C only:

  • Fasting TG 90 - 150 mg/dL at Screening
  • Fasting LDL-C > 70 mg/dL at Screening

Inclusion Criteria for Cohort EE Only:

  • Homozygous FH diagnosis and fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L)

Inclusion Criteria for Cohort FF Only:

  • Heterozygous FH diagnosis and fasting LDL-C ≥ 160 mg/dL (4.1 mmol/L)

Inclusion Criteria for Cohorts EE and FF Only:

  • Maximally tolerated stable LDL-C lowering agents (stable for at least 12 weeks)
  • On stable low-fat diet
  • Stable weight (± 4 kg) for ≥ 6 weeks prior to screening

Exclusion Criteria for All Cohorts:

  • Known history or positive test for HIV, HCV, or HBV
  • Treatment with another Study Drug, biological agent, or device within one-month or 5-half-lives of screening
  • Regular use of alcohol within 6 months of screening
  • Use of concomitant drugs unless authorized by the Sponsor Medical Monitor
  • Known contraindication and/or allergy to heparin
  • Smoking > 10 cigarettes a day
  • Considered unsuitable for inclusion by the Principal Investigator

Exclusion Criteria for Cohorts EE and FF:

  • Myocardial infarction, percutaneous transluminal coronary intervention, or coronary artery bypass graft surgery within 12 weeks prior to screening, or cerebrovascular accident within 24 weeks prior to screening. Subjects with adequately treated stable angina, per Investigator assessment, may be included
  • Congestive heart failure defined by NYHA Classes III or IV
  • T2DM with HbA1c > 8.0%
  • Prior treatment with gene therapy
  • Currently receiving apheresis treatments or last apheresis treatment was within 8 weeks of screening
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02709850


Contacts
Contact: Ionis Pharmaceuticals 800-679-4747 patients@ionisph.com

Locations
Canada, Ontario
Clinical Site Recruiting
Toronto, Ontario, Canada, M9L 3A2
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
Akcea Therapeutics
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02709850     History of Changes
Other Study ID Numbers: IONIS ANGPTL3-LRx
First Submitted: November 22, 2015
First Posted: March 16, 2016
Last Update Posted: May 10, 2017
Last Verified: May 2017

Keywords provided by Ionis Pharmaceuticals, Inc.:
ANGPTL-3

Additional relevant MeSH terms:
Hypercholesterolemia
Hypertriglyceridemia
Hyperlipoproteinemia Type II
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias
Riboflavin
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Photosensitizing Agents
Dermatologic Agents