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

Phase 2

Completed

Conditions: Hypertriglyceridemia
Cardiovascular Diseases

Interventions: Drug: Placebo
Drug: ISIS 678354

Registration Number: NCT03385239

Lead Sponsor: Akcea Therapeutics

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 114

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pooled Placebo	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).
Cohort A: ISIS 678354: 10 mg Q4W	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: ISIS 678354: 15 mg Q2W	ISIS 678354	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 B: ISIS 678354: 50 mg Q4W	ISIS 678354	Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.
Cohort D: ISIS 678354: 10 mg QW	ISIS 678354	Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point	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)	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

Name	Time	Method
Maximum Plasma Concentration (Cmax) of ISIS 678354	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)
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])	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.
Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354	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	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)
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	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) <= 100 mg/dL (<= 1.13 mmol/L)	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.