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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02709850
Recruitment Status : Completed
First Posted : March 16, 2016
Last Update Posted : November 19, 2020
Sponsor:
Collaborator:
Akcea Therapeutics
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Study Description
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Brief Summary:
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 or disease Intervention/treatment Phase
Hypertriglyceridemia Familial Hypercholesterolemia Drug: IONIS ANGPTL3-LRx Drug: Placebo Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
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
Actual Study Start Date : November 30, 2015
Actual Primary Completion Date : April 12, 2017
Actual Study Completion Date : June 26, 2017

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Cohorts A, D: Placebo
Participants received a single-dose of IONIS ANGPTL3-LRx-matching placebo subcutaneously on Day 1.
 Drug: Placebo
0.9%NaCl, water, riboflavin
Experimental: Cohorts A, D: IONIS ANGPTL3-LRx 20 mg
Participants received a single-dose of IONIS ANGPTL3-LRx 20 milligrams (mg) subcutaneously on Day 1.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Experimental: Cohorts A, D: IONIS ANGPTL3-LRx 120 mg
Participants received a single-dose of IONIS ANGPTL3-LRx 120 mg subcutaneously on Day 1.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Placebo Comparator: Cohorts B, C: Placebo
Participants received a single-dose of IONIS ANGPTL3-LRx-matching placebo subcutaneously on Day 1.
 Drug: Placebo
0.9%NaCl, water, riboflavin
Experimental: Cohorts B, C: IONIS ANGPTL3-LRx 40 mg
Participants received a single-dose of IONIS ANGPTL3-LRx 40 mg subcutaneously on Day 1.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Experimental: Cohorts B, C: IONIS ANGPTL3-LRx 80 mg
Participants received a single-dose of IONIS ANGPTL3-LRx 80 mg subcutaneously on Day 1.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Placebo Comparator: Cohorts AA-DD: Placebo
Participants received IONIS ANGPTL3-LRx-matching placebo subcutaneously once per week for 6 weeks.
 Drug: Placebo
0.9%NaCl, water, riboflavin
Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 10 mg
Participants received IONIS ANGPTL3-LRx 10 mg subcutaneously once per week for 6 weeks.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 20 mg
Participants received IONIS ANGPTL3-LRx 20 mg subcutaneously once per week for 6 weeks.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 40 mg
Participants received IONIS ANGPTL3-LRx 40 mg subcutaneously once per week for 6 weeks.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802
Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 60 mg
Participants received IONIS ANGPTL3-LRx 60 mg subcutaneously once per week for 6 weeks.
 Drug: IONIS ANGPTL3-LRx
Other Name: ISIS 703802


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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 :
  1. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older 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
  • Body Mass Index (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 triglycerides (TG) ≥ 150 mg/dL at Screening
  • Fasting low density lipoprotein cholesterol (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 Human Immunodeficiency Virus (HIV), Hepatitis C (HCV), or Hepatitis B (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. Participants with adequately treated stable angina, per Investigator assessment, may be included
  • Congestive heart failure defined by NYHA Classes III or IV
  • Type 2 diabetes mellitus (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
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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


Locations
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Canada, Ontario
Clinical Site
Toronto, Ontario, Canada, M9L 3A2
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
Akcea Therapeutics
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02709850    
Other Study ID Numbers: ISIS 703802-CS1
2015-004003-23 ( EudraCT Number )
First Posted: March 16, 2016    Key Record Dates
Last Update Posted: November 19, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ionis Pharmaceuticals, Inc.:
ANGPTL-3
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type II
Hypercholesterolemia
Hypertriglyceridemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
 Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias