A Study of Olezarsen (ISIS 678354) in Participants With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease, or With Severe Hypertriglyceridemia

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo in participants with hypertriglyceridemia and atherosclerotic cardiovascular disease, or with severe hypertriglyceridemia.

Detailed Description
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This is a Phase 3, multi-center, placebo-controlled study of up to 1312 participants with hypertriglyceridemia and atherosclerotic cardiovascular disease. The study consists of 3 periods: 1) Screening Period: Week -12 to Week -1 (up to 12 weeks); 2) Treatment Period up to Week 53; and 3) Post-Treatment Follow-up Period: Week 54 to Week 66 (13 weeks). Participants enrolled will receive olezarsen or placebo once every 4 weeks during the 53-week Treatment Period. The Screening Period was extended with no impact to overall study timelines. Endpoints added to provide assessment on the pancreatitis rate after olezarsen reaches steady state levels. A coronary computed tomographic angiography (CTA) sub study will be performed to assess whether triglyceride lowering through inhibition of apoC-III protein synthesis may reduce coronary plaque progression.

Official Title
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A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study of Olezarsen (ISIS 678354) in Patients With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), or With Severe Hypertriglyceridemia

Conditions
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Hypertriglyceridemia, Cardiovascular Diseases, Atherosclerosis

Intervention / Treatment
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* Drug: Olezarsen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must fall into 1 of the following groups (a or b): a. Hypertriglyceridemia with fasting TG ≥200 mg/dL (2.26 millimoles per liter [mmol/L]) and <500 mg/dL (5.65 mmol/L) with either Clinical diagnosis of atherosclerotic cardiovascular disease (ASCVD) or At increased risk for ASCVD b. Severe hypertriglyceridemia with fasting TG ≥500 mg/dL (5.65 mmol/L) Participants should be on standard of care (SOC) lipid-lowering medications per local guidelines. Lipid-lowering medications should be optimized and stabilized for at least 4 weeks prior to Screening to minimize changes in these medications during the study. Exclusion Criteria: Hemoglobin A1c (HbA1c) ≥ 9.5% at Screening Alanine aminotransferase or aspartate aminotransferase > 3.0 × upper limit of normal Total bilirubin > 1.5 upper limit of normal unless due to Gilbert's syndrome Estimated GFR < 30 mL/min/1.73 m^2 NOTE: Other Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olezarsen<br>Participants will be randomized to receive multiple doses of olezarsen, once every 4 weeks by subcutaneous (SC) injection for up to Week 49. | Drug: Olezarsen<br>* Olezarsen will be administered by SC injection.<br>* Other names: AKCEA-APOCIII-LRx;|
| Placebo Comparator: Placebo<br>Participants will be randomized to receive olezarsen-matching placebo, once every 4 weeks by SC injection for up to Week 49. | Drug: Placebo<br>* Olezarsen-matching placebo will be administered by SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 25 in Fasting Triglycerides (TG) Compared to Placebo |  | Baseline to Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 53 in Fasting TG Compared to Placebo |  | Baseline to Week 53 | 
| Proportion of Participants who Achieve Fasting TG <150 Milligrams per Deciliter (mg/dL) at Weeks 25 and 53 Compared to Placebo |  | Baseline, Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Apolipoprotein C-III (apoC-III) Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Very Low-Density Lipoprotein-Cholesterol (VLDL)-C Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Remnant Cholesterol Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting non-High Density Lipoprotein-Cholesterol (HDL)-C Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting High-Density Lipoprotein-Cholesterol (HDL)-C Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Total Cholesterol (TC) Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Apolipoprotein B (apoB) Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Apolipoprotein B-48 (apoB-48) Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Low-Density Lipoprotein-Cholesterol (LDL)-C Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Percent Change From Baseline to Weeks 25 and 53 in Fasting Apolipoprotein A-1 (apoA-1) Compared to Placebo |  | Baseline to Weeks 25 and 53 | 
| Adjudicated Acute Pancreatitis Event Rate During the Treatment Period Compared to Placebo in Participants With ≥ 2 Events of Adjudicated Acute Pancreatitis in 5 Years Prior to Enrollment |  | Week 1 through Week 53 | 
| Adjudicated Acute Pancreatitis Event Rate from Week 13 to Week 53 Compared to Placebo in Participants With ≥ 2 Events of Adjudicated Acute Pancreatitis in 5 Years Prior to Enrollment |  | Week 13 through Week 53 | 
| Adjudicated Acute Pancreatitis Event Rate During the Treatment Period Compared to Placebo |  | Week 1 through Week 53 | 
| Adjudicated Acute Pancreatitis Event Rate from Week 13 to Week 53 Compared to Placebo |  | Week 13 through Week 53 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ISIS 678354, Olezarsen