Back to resultsStudy of ISIS 678354 (AKCEA-APOCIII-LRx) in Participants With Hypertriglyceridemia and Established Cardiovascular Disease (CVD)
Primary Purpose
Hypertriglyceridemia, Cardiovascular Diseases
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ISIS 678354
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hypertriglyceridemia focused on measuring AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx, Dyslipidemia, Metabolic Disease, Hyperlipidemia, Cardiac Disease, Lipid Metabolism Disorders, Triglycerides High, Vascular Diseases
Eligibility Criteria
Key Inclusion Criteria:
- Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, or peripheral artery disease).
- Fasting serum triglycerides (TG) greater than or equal to (≥) 200 milligrams per deciliter (mg/dL) (≥ 2.3 millimoles per liter (mmol/L)) and less than or equal to (≤) 500 mg/dL (≥ 5.7 mmol/L) at Screening.
- Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit.
- Must be on standard-of-care preventative therapy for known CVD risk factors.
Key Exclusion Criteria:
- Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack (TIA).
- Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis.
- Heart failure New York Heart Association (NYHA) class IV.
- Type 1 diabetes mellitus.
Type 2 diabetes mellitus with any of the following:
- Newly diagnosed within 12 weeks of Screening.
- Glycated hemoglobin (HbA1c) ≥ 9.0% at Screening.
- Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new medication within 12 weeks of Screening [with the exception of ± 10 units of insulin].
- Body Mass Index (BMI) greater than (>) 40 kilograms per square meter (kg/m^2).
Sites / Locations
- Clinical Site
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- Clinical Site
- Clinical Site
- Clinical Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Placebo Comparator
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
Pooled Placebo
Cohort A: ISIS 678354: 10 mg Q4W
Cohort C: ISIS 678354: 15 mg Q2W
Cohort D: ISIS 678354: 10 mg QW
Cohort B: ISIS 678354: 50 mg Q4W
Arm Description
Participants in each cohort (A, B, C and D) were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354).
Cohort A participants received 10 milligrams (mg) ISIS 678354, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses.
Cohort C participants received 15 mg ISIS 678354, SC injection, once every 2 weeks (Q2W) for up to 51 weeks and a maximum of 26 doses.
Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses.
Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.
Outcomes
Primary Outcome Measures
Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
An analysis of covariance (ANCOVA) model was performed on the log ratio of TG value at the Primary Analysis Time Point to TG value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: (ratio of TG value at the Primary Analysis Time Point to TG value at Baseline - 1) × 100.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered to be related to the investigational drug product. A TEAE was defined as any AE starting on or after the first dose of the study drug.
Secondary Outcome Measures
Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point
An ANCOVA model was performed on the log ratio of Primary Analysis Time Point value to Baseline value for ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I. The estimate of the log ratio was converted back to the original scale and percent change for each lipid parameter was calculated using formula: (ratio of Primary Analysis Time Point value to Baseline value - 1) × 100.
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])
The percentage of participants who achieved <= 150 mg/dL or <= 1.7 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)
The percentage of participants who achieved <= 100 mg/dL or <= 1.13 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Maximum Plasma Concentration (Cmax) of ISIS 678354
Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354
Full Information
NCT ID
NCT03385239
First Posted
December 1, 2017
Last Updated
December 19, 2022
Sponsor
Akcea Therapeutics
Collaborators
Ionis Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT03385239
Brief Title
Study of ISIS 678354 (AKCEA-APOCIII-LRx) in Participants With Hypertriglyceridemia and Established Cardiovascular Disease (CVD)
Official Title
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 678354 Administered Subcutaneously to Patients With Hypertriglyceridemia and Established Cardiovascular Disease (CVD) or at a High Risk for CVD
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
January 30, 2018 (Actual)
Primary Completion Date
November 25, 2019 (Actual)
Study Completion Date
February 25, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Akcea Therapeutics
Collaborators
Ionis Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride (TG) levels in participants with hypertriglyceridemia and established CVD or at a high risk for CVD.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertriglyceridemia, Cardiovascular Diseases
Keywords
AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx, Dyslipidemia, Metabolic Disease, Hyperlipidemia, Cardiac Disease, Lipid Metabolism Disorders, Triglycerides High, Vascular Diseases
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
114 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pooled Placebo
Arm Type
Placebo Comparator
Arm Description
Participants in each cohort (A, B, C and D) were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354).
Arm Title
Cohort A: ISIS 678354: 10 mg Q4W
Arm Type
Experimental
Arm Description
Cohort A participants received 10 milligrams (mg) ISIS 678354, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses.
Arm Title
Cohort C: ISIS 678354: 15 mg Q2W
Arm Type
Experimental
Arm Description
Cohort C participants received 15 mg ISIS 678354, SC injection, once every 2 weeks (Q2W) for up to 51 weeks and a maximum of 26 doses.
Arm Title
Cohort D: ISIS 678354: 10 mg QW
Arm Type
Experimental
Arm Description
Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses.
Arm Title
Cohort B: ISIS 678354: 50 mg Q4W
Arm Type
Placebo Comparator
Arm Description
Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.
Intervention Type
Drug
Intervention Name(s)
ISIS 678354
Other Intervention Name(s)
AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Intervention Description
ISIS 678354 solution for SC injection.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Sterile Normal Saline (0.9% NaCl).
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
Description
An analysis of covariance (ANCOVA) model was performed on the log ratio of TG value at the Primary Analysis Time Point to TG value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: (ratio of TG value at the Primary Analysis Time Point to TG value at Baseline - 1) × 100.
Time Frame
Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered to be related to the investigational drug product. A TEAE was defined as any AE starting on or after the first dose of the study drug.
Time Frame
Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)
Secondary Outcome Measure Information:
Title
Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point
Description
An ANCOVA model was performed on the log ratio of Primary Analysis Time Point value to Baseline value for ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I. The estimate of the log ratio was converted back to the original scale and percent change for each lipid parameter was calculated using formula: (ratio of Primary Analysis Time Point value to Baseline value - 1) × 100.
Time Frame
Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Title
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])
Description
The percentage of participants who achieved <= 150 mg/dL or <= 1.7 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Time Frame
Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Title
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)
Description
The percentage of participants who achieved <= 100 mg/dL or <= 1.13 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Time Frame
Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Title
Maximum Plasma Concentration (Cmax) of ISIS 678354
Time Frame
Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
Title
Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354
Time Frame
Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
Title
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354
Time Frame
Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, or peripheral artery disease).
Fasting serum triglycerides (TG) greater than or equal to (≥) 200 milligrams per deciliter (mg/dL) (≥ 2.3 millimoles per liter (mmol/L)) and less than or equal to (≤) 500 mg/dL (≥ 5.7 mmol/L) at Screening.
Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit.
Must be on standard-of-care preventative therapy for known CVD risk factors.
Key Exclusion Criteria:
Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack (TIA).
Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis.
Heart failure New York Heart Association (NYHA) class IV.
Type 1 diabetes mellitus.
Type 2 diabetes mellitus with any of the following:
Newly diagnosed within 12 weeks of Screening.
Glycated hemoglobin (HbA1c) ≥ 9.0% at Screening.
Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new medication within 12 weeks of Screening [with the exception of ± 10 units of insulin].
Body Mass Index (BMI) greater than (>) 40 kilograms per square meter (kg/m^2).
Facility Information:
Facility Name
Clinical Site
City
Cottonwood
State/Province
Arizona
ZIP/Postal Code
86326
Country
United States
Facility Name
Clinical Site
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
Clinical Site
City
Carmichael
State/Province
California
ZIP/Postal Code
95608
Country
United States
Facility Name
Clinical Site
City
Fresno
State/Province
California
ZIP/Postal Code
93720
Country
United States
Facility Name
Clinical Site
City
La Jolla
State/Province
California
ZIP/Postal Code
92037-7410
Country
United States
Facility Name
Clinical Site
City
Long Beach
State/Province
California
ZIP/Postal Code
90807
Country
United States
Facility Name
Clinical Site
City
Montclair
State/Province
California
ZIP/Postal Code
91763
Country
United States
Facility Name
Clinical Site
City
Wilmington
State/Province
Delaware
ZIP/Postal Code
19803
Country
United States
Facility Name
Clinical Site
City
Boca Raton
State/Province
Florida
ZIP/Postal Code
33434
Country
United States
Facility Name
Clinical Site
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32216
Country
United States
Facility Name
Clinical Site
City
New Port Richey
State/Province
Florida
ZIP/Postal Code
34652
Country
United States
Facility Name
Clinical Site
City
Munster
State/Province
Indiana
ZIP/Postal Code
46321
Country
United States
Facility Name
Clinical Site
City
Ames
State/Province
Iowa
ZIP/Postal Code
50010
Country
United States
Facility Name
Clinical Site
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Clinical Site
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40213
Country
United States
Facility Name
Clinical Site
City
Fall River
State/Province
Massachusetts
ZIP/Postal Code
02721
Country
United States
Facility Name
Clinical Site
City
Cooperstown
State/Province
New York
ZIP/Postal Code
13326
Country
United States
Facility Name
Clinical Site
City
High Point
State/Province
North Carolina
ZIP/Postal Code
27262
Country
United States
Facility Name
Clinical Site
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Clinical Site
City
Lansdale
State/Province
Pennsylvania
ZIP/Postal Code
19446
Country
United States
Facility Name
Clinical Site
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02906
Country
United States
Facility Name
Clinical Site
City
Greer
State/Province
South Carolina
ZIP/Postal Code
29651
Country
United States
Facility Name
Clinical Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Clinical Site
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53215
Country
United States
Facility Name
Clinical Site
City
Cambridge
State/Province
Ontario
ZIP/Postal Code
N1R 6V6
Country
Canada
Facility Name
Clinical Site
City
Sudbury
State/Province
Ontario
ZIP/Postal Code
P3E 5M4
Country
Canada
Facility Name
Clinical Site
City
Brossard
State/Province
Quebec
ZIP/Postal Code
J4Z 2K9
Country
Canada
Facility Name
Clinical Site
City
Chicoutimi
State/Province
Quebec
Country
Canada
Facility Name
Clinical Site
City
Gatineau
State/Province
Quebec
ZIP/Postal Code
J8Y 6S8
Country
Canada
Facility Name
Clinical Site
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H1T 1C8
Country
Canada
Facility Name
Clinical Site
City
Québec
State/Province
Quebec
ZIP/Postal Code
G1V 4W2
Country
Canada
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35025993
Citation
Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O'Dea LSL, Tsimikas S, Gaudet D. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820.
Results Reference
derived
Learn more about this trial
Study of ISIS 678354 (AKCEA-APOCIII-LRx) in Participants With Hypertriglyceridemia and Established Cardiovascular Disease (CVD)
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