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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hypertriglyceridemia, Cardiovascular Diseases

Intervention / Treatment
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* Drug: ISIS 678354
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Pooled Placebo<br>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<br>* Sterile Normal Saline (0.9% NaCl).<br>|
| Experimental: Cohort A: ISIS 678354: 10 mg Q4W<br>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<br>* ISIS 678354 solution for SC injection.<br>* Other names: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx;|
| Experimental: Cohort C: ISIS 678354: 15 mg Q2W<br>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<br>* ISIS 678354 solution for SC injection.<br>* Other names: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx;|
| Experimental: Cohort D: ISIS 678354: 10 mg QW<br>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<br>* ISIS 678354 solution for SC injection.<br>* Other names: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx;|
| Placebo Comparator: Cohort B: ISIS 678354: 50 mg Q4W<br>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<br>* ISIS 678354 solution for SC injection.<br>* Other names: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | 
| 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. | Up to the 13-week post-treatment follow-up period (Up to approximately 15 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | 
| 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. | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | 
| 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. | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx, Dyslipidemia, Metabolic Disease, Hyperlipidemia, Cardiac Disease, Lipid Metabolism Disorders, Triglycerides High, Vascular Diseases