A Study of Olezarsen (ISIS 678354) Administered to Participants With Severe Hypertriglyceridemia

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the efficacy of olezarsen as compared to placebo on the percent change in fasting triglycerides (TG) from baseline.

Detailed Description
-----------------
This is a multi-center, randomized, double-blind, placebo-controlled study in up to approximately 540 participants. Participants will be randomized to receive olezarsen or placebo in a 53-week treatment period. The length of participation in the study will be approximately 78 weeks, which includes an up to 12-week screening period, a 53-week treatment period, and a 13-week post-treatment evaluation period or transition to open-label extension (OLE) study with up to 1-year treatment. 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.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of ISIS 678354 Administered Subcutaneously to Patients With Severe Hypertriglyceridemia

Conditions
-----------------
Severe Hypertriglyceridemia

Intervention / Treatment
-----------------
* Drug: Olezarsen
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Fasting TG ≥ 500 mg/dL (5.65 mmol/L) at Screening and Qualification Patients must be on lipid-lowering therapy that should adhere to standard of care (SOC) 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. Key Exclusion Criteria: Hemoglobin A1c (HbA1c) ≥ 9.5% at Screening Alanine aminotransferase or aspartate aminotransferase > 3.0 × upper limit of normal Total bilirubin > upper limit of normal unless due to Gilbert's syndrome Estimated GFR < 30 mL/min/1.73 m^2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olezarsen<br>Olezarsen will be administered once every 4 weeks by subcutaneous (SC) injection from Week 1 through Week 49. | Drug: Olezarsen<br>* Olezarsen will be administered by SC injection.<br>* Other names: ISIS 678354;|
| Placebo Comparator: Placebo<br>Olezarsen-matching placebo will be administered once every 4 weeks by SC injection from Week 1 through Week 49. | Drug: Placebo<br>* Olezarsen-matching placebo will be administered by SC injection.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Fasting TG at 6 Months (Average of Weeks 25 and 27) Compared to Placebo |  | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Fasting TG at 12 Months (Average of Weeks 51 and 53) Compared to Placebo |  | Baseline and Month 12 | 
| Proportion of Participants Who Achieve Fasting TG Less Than (<) 500 milligrams per deciliter (mg/dL) (5.7 millimoles per liter [mmol/L]) at 6 and 12 Months Compared to Placebo |  | Month 6 and 12 | 
| Proportion of Participants Who Achieve Fasting TG < 880 mg/dL (10 mmol/L) at 6 and 12 Months Compared to Placebo in the Subgroup of Participants with Baseline TG ≥ 880 mg/dL |  | Month 6 and 12 | 
| Proportion of Participants Who Achieve Fasting TG < 1000 mg/dL (11.29 mmol/L) at 6 and 12 Months Compared to Placebo in the Subgroup of Participants with Baseline TG ≥ 1000 mg/dL |  | Month 6 and Month 12 | 
| Percent Change from Baseline in Fasting Apolipoprotein C-III (ApoC-III) at 6 and 12 Months Compared to Placebo |  | Baseline, Month 6 and 12 | 
| Percent Change from Baseline in Fasting Very Low-Density Lipoprotein Cholesterol (VLDL-C) at 6 and 12 Months Compared to Placebo |  | Baseline, Month 6 and 12 | 
| Percent Change from Baseline in Fasting Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at 6 and 12 Months Compared to Placebo |  | Baseline, Month 6 and 12 | 
| Percent Change from Baseline in Fasting High-Density Lipoprotein-Cholesterol (HDL-C) at 6 and 12 Months Compared to Placebo |  | Baseline, Month 6 and 12 | 
| 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ISIS 678354, Fasting Triglycerides, Apolipoprotein C-III, Very Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein-Cholesterol, Non-High-Density Lipoprotein-Cholesterol, Olezarsen