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Study of ISIS 678354 (AKCEA-APOCIII-LRx) in Participants With Hypertriglyceridemia and Established Cardiovascular Disease (CVD)

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ClinicalTrials.gov Identifier: NCT03385239
Recruitment Status : Completed
First Posted : December 28, 2017
Results First Posted : January 11, 2023
Last Update Posted : January 11, 2023
Sponsor:
Collaborator:
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Akcea Therapeutics

Study Description
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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.

Condition or disease Intervention/treatment Phase
Hypertriglyceridemia Cardiovascular Diseases Drug: ISIS 678354 Drug: Placebo Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 114 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : January 30, 2018
Actual Primary Completion Date : November 25, 2019
Actual Study Completion Date : February 25, 2020
Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Pooled Placebo
Participants in each cohort (A, B, C and D) were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354).
 Drug: Placebo
Sterile Normal Saline (0.9% NaCl).
Experimental: Cohort A: ISIS 678354: 10 mg Q4W
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.
 Drug: ISIS 678354
ISIS 678354 solution for SC injection.
Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Experimental: Cohort C: ISIS 678354: 15 mg Q2W
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.
 Drug: ISIS 678354
ISIS 678354 solution for SC injection.
Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Experimental: Cohort D: ISIS 678354: 10 mg QW
Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses.
 Drug: ISIS 678354
ISIS 678354 solution for SC injection.
Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx
Placebo Comparator: Cohort B: ISIS 678354: 50 mg Q4W
Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.
 Drug: ISIS 678354
ISIS 678354 solution for SC injection.
Other Name: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx


Outcome Measures
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Primary Outcome Measures :
  1. Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) ]
    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.

  2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to the 13-week post-treatment follow-up period (Up to approximately 15 months) ]
    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 :
  1. 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 [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) ]
    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.

  2. Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) ]
    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.

  3. Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) ]
    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.

  4. 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) ]
  5. 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) ]
  6. 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) ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).
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): NCT03385239


Locations
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United States, Arizona
Clinical Site
Cottonwood, Arizona, United States, 86326
United States, Arkansas
Clinical Site
Little Rock, Arkansas, United States, 72205
United States, California
Clinical Site
Carmichael, California, United States, 95608
Clinical Site
Fresno, California, United States, 93720
Clinical Site
La Jolla, California, United States, 92037-7410
Clinical Site
Long Beach, California, United States, 90807
Clinical Site
Montclair, California, United States, 91763
United States, Delaware
Clinical Site
Wilmington, Delaware, United States, 19803
United States, Florida
Clinical Site
Boca Raton, Florida, United States, 33434
Clinical Site
Jacksonville, Florida, United States, 32216
Clinical Site
New Port Richey, Florida, United States, 34652
United States, Indiana
Clinical Site
Munster, Indiana, United States, 46321
United States, Iowa
Clinical Site
Ames, Iowa, United States, 50010
United States, Kansas
Clinical Site
Kansas City, Kansas, United States, 66160
United States, Kentucky
Clinical Site
Louisville, Kentucky, United States, 40213
United States, Massachusetts
Clinical Site
Fall River, Massachusetts, United States, 02721
United States, New York
Clinical Site
Cooperstown, New York, United States, 13326
United States, North Carolina
Clinical Site
High Point, North Carolina, United States, 27262
United States, Oregon
Clinical Site
Portland, Oregon, United States, 97239
United States, Pennsylvania
Clinical Site
Lansdale, Pennsylvania, United States, 19446
United States, Rhode Island
Clinical Site
Providence, Rhode Island, United States, 02906
United States, South Carolina
Clinical Site
Greer, South Carolina, United States, 29651
United States, Texas
Clinical Site
Houston, Texas, United States, 77030
United States, Wisconsin
Clinical Site
Milwaukee, Wisconsin, United States, 53215
Canada, Ontario
Clinical Site
Cambridge, Ontario, Canada, N1R 6V6
Clinical Site
Sudbury, Ontario, Canada, P3E 5M4
Canada, Quebec
Clinical Site
Brossard, Quebec, Canada, J4Z 2K9
Clinical Site
Chicoutimi, Quebec, Canada
Clinical Site
Gatineau, Quebec, Canada, J8Y 6S8
Clinical Site
Montréal, Quebec, Canada, H1T 1C8
Clinical Site
Québec, Quebec, Canada, G1V 4W2
Sponsors and Collaborators
Akcea Therapeutics
Ionis Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Akcea Therapeutics:
Study Protocol and Statistical Analysis Plan  [PDF] December 17, 2019

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Akcea Therapeutics
ClinicalTrials.gov Identifier: NCT03385239    
Other Study ID Numbers: ISIS 678354-CS2
First Posted: December 28, 2017    Key Record Dates
Results First Posted: January 11, 2023
Last Update Posted: January 11, 2023
Last Verified: December 2022
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 Akcea Therapeutics:
AKCEA-APOCIII-LRx
IONIS-APOCIII-LRx
Dyslipidemia
Metabolic Disease
Hyperlipidemia
 Cardiac Disease
Lipid Metabolism Disorders
Triglycerides High
Vascular Diseases
Additional relevant MeSH terms:
Layout table for MeSH terms
Cardiovascular Diseases
Hypertriglyceridemia
Hyperlipidemias
 Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases