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
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Condition or disease | Intervention/treatment | Phase |
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Hypertriglyceridemia Cardiovascular Diseases | Drug: ISIS 678354 Drug: Placebo | Phase 2 |
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 |
Arm | Intervention/treatment |
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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).
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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.
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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.
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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.
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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 |
- 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.
- 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.
- 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.
- 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.
- 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.
- 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) ]
- 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) ]
- 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) ]

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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 |
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.
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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).

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
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 |
Documents provided by Akcea Therapeutics:
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 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
AKCEA-APOCIII-LRx IONIS-APOCIII-LRx Dyslipidemia Metabolic Disease Hyperlipidemia |
Cardiac Disease Lipid Metabolism Disorders Triglycerides High Vascular Diseases |
Cardiovascular Diseases Hypertriglyceridemia Hyperlipidemias |
Dyslipidemias Lipid Metabolism Disorders Metabolic Diseases |