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Safety, Tolerability, PK, and Pharmacodynamics(PD) of IONIS APOCIII-LRx in Healthy Volunteers With Elevated Triglycerides

Primary Purpose

Elevated Triglycerides (TG)

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
APOC-III-L-Rx
Placebo Comparator
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Elevated Triglycerides (TG)

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Must have given written informed consent and be able to comply with all study requirements
  • Healthy males or females aged 18-65 inclusive
  • Females must be non-pregnant and non-lactating, and either surgically sterile or post- menopausal
  • Males must be surgically sterile, abstinent or using an acceptable contraceptive method
  • BMI < 35.0 kg/m2
  • Subjects must have Fasting TG ≥ 90 mg/dL or ≥ 200 mg/dL depending on Cohort assignment

Exclusion Criteria:

  • Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
  • Treatment with another Study Drug, biological agent, or device within one-month of screening
  • Regular excessive use of alcohol within 6 months of Screening
  • Use of concomitant drugs unless authorized by the Sponsor Medical Monitor
  • Smoking > 10 cigarettes a day
  • Considered unsuitable for inclusion by the Principal Investigator

Sites / Locations

  • BioPharma Services

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

IONIS-APOC-III-LRx

Placebo (Normal Saline)

Arm Description

Ascending single and multiple doses of IONIS-APOC-III-LRx by subcutaneous (SC) injection

Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator

Outcomes

Primary Outcome Measures

To evaluate the safety and tolerability of single and multiple doses of IONIS- APOC-III-LRx - (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters)
The safety and tolerability of IONIS- APOC-III-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 APOC-III-LRx will be compared with those from subjects dosed with placebo.

Secondary Outcome Measures

To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx
The maximum area under the curve (AUC) of IONIS- APOC-III-LRx will be assessed following single and multiple- dose SC administration
To evaluate the urine pharmacokinetics of single and multiple doses of IONIS¬-APOC-III-LRx
The amount of IONIS-APOC-III-LRx excreted in urine at selected 24-hour intervals [Ae0-24h] will be determined.
To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx
The maximum plasma concentration (Cmax) of IONIS- APOC-III-LRx will be assessed following single and multiple- dose SC administration
To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx
The maximum time to Cmax (Tmax) of IONIS- APOC-III-LRx will be assessed following single and multiple-dose SC administration

Full Information

First Posted
August 23, 2016
Last Updated
May 18, 2018
Sponsor
Ionis Pharmaceuticals, Inc.
Collaborators
Akcea Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT02900027
Brief Title
Safety, Tolerability, PK, and Pharmacodynamics(PD) of IONIS APOCIII-LRx in Healthy Volunteers With Elevated Triglycerides
Official Title
Placebo-Controlled, Dose-Escalation Study to Assess Safety, Tolerability, PK and PD of a GalNAc3 Conjugated Antisense Oligonucleotide Targeting ApoC-III, Administered Subcutaneously to Healthy Volunteers With Elevated Triglycerides
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
September 2016 (Actual)
Primary Completion Date
April 30, 2018 (Actual)
Study Completion Date
April 30, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.
Collaborators
Akcea Therapeutics

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS APOC-III-LRx given to healthy volunteer subjects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Elevated Triglycerides (TG)

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
56 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IONIS-APOC-III-LRx
Arm Type
Experimental
Arm Description
Ascending single and multiple doses of IONIS-APOC-III-LRx by subcutaneous (SC) injection
Arm Title
Placebo (Normal Saline)
Arm Type
Placebo Comparator
Arm Description
Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator
Intervention Type
Drug
Intervention Name(s)
APOC-III-L-Rx
Intervention Description
Ascending single and multiple doses of IONIS-APOC-III-LRx by subcutaneous (SC) injection
Intervention Type
Drug
Intervention Name(s)
Placebo Comparator
Intervention Description
Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator
Primary Outcome Measure Information:
Title
To evaluate the safety and tolerability of single and multiple doses of IONIS- APOC-III-LRx - (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters)
Description
The safety and tolerability of IONIS- APOC-III-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 APOC-III-LRx will be compared with those from subjects dosed with placebo.
Time Frame
Up to 183 days
Secondary Outcome Measure Information:
Title
To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx
Description
The maximum area under the curve (AUC) of IONIS- APOC-III-LRx will be assessed following single and multiple- dose SC administration
Time Frame
Up to 183 days
Title
To evaluate the urine pharmacokinetics of single and multiple doses of IONIS¬-APOC-III-LRx
Description
The amount of IONIS-APOC-III-LRx excreted in urine at selected 24-hour intervals [Ae0-24h] will be determined.
Time Frame
Up to 183 days
Title
To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx
Description
The maximum plasma concentration (Cmax) of IONIS- APOC-III-LRx will be assessed following single and multiple- dose SC administration
Time Frame
Up to 183 Days
Title
To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx
Description
The maximum time to Cmax (Tmax) of IONIS- APOC-III-LRx will be assessed following single and multiple-dose SC administration
Time Frame
Up to 183 days
Other Pre-specified Outcome Measures:
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with plasma apolipoprotein C-III (apoC-III) compared to baseline.
Time Frame
Up to 183 days
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with TG compared to baseline.
Time Frame
Up to 183 days
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with total cholesterol (TC) compared to baseline.
Time Frame
Up to 183 days
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with low density lipoprotein cholesterol (LDL-C) compared to baseline.
Time Frame
Up to 183 days
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with high density lipoprotein cholesterol (HDL-C) compared to baseline.
Time Frame
Up to 183 days
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with non-high density lipoprotein cholesterol (non-HDL-C) compared to baseline.
Time Frame
Up to 183 days
Title
Exploratory pharmacodynamic effects of IONIS-APOC-III-LRx
Description
Effects of IONIS-APOC-III-LRx on changes in levels of oxidized phospholipids associated with very low density lipoprotein cholesterol (VLDL-C) compared to baseline.
Time Frame
Up to 183 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Must have given written informed consent and be able to comply with all study requirements Healthy males or females aged 18-65 inclusive Females must be non-pregnant and non-lactating, and either surgically sterile or post- menopausal Males must be surgically sterile, abstinent or using an acceptable contraceptive method BMI < 35.0 kg/m2 Subjects must have Fasting TG ≥ 90 mg/dL or ≥ 200 mg/dL depending on Cohort assignment Exclusion Criteria: Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B Treatment with another Study Drug, biological agent, or device within one-month of screening Regular excessive use of alcohol within 6 months of Screening Use of concomitant drugs unless authorized by the Sponsor Medical Monitor Smoking > 10 cigarettes a day Considered unsuitable for inclusion by the Principal Investigator
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janice Faulknor
Organizational Affiliation
BioPharma Services
Official's Role
Principal Investigator
Facility Information:
Facility Name
BioPharma Services
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M9L 3A2
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
31329855
Citation
Alexander VJ, Xia S, Hurh E, Hughes SG, O'Dea L, Geary RS, Witztum JL, Tsimikas S. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 2019 Sep 1;40(33):2785-2796. doi: 10.1093/eurheartj/ehz209.
Results Reference
derived

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Safety, Tolerability, PK, and Pharmacodynamics(PD) of IONIS APOCIII-LRx in Healthy Volunteers With Elevated Triglycerides

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