A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) in Adults With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), and/or With Severe Hypertriglyceridemia

A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of ISIS 678354 in Patients With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), and/or With Severe Hypertriglyceridemia

The purpose of the study is to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo at Months 6 and 12 and the percentage of participants who achieve different thresholds in fasting TG. Another objective is to evaluate the effect of olezarsen on percent change in fasting apolipoprotein C-III (apoC-III), very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, total cholesterol (TC), apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein A-1 (apoA-1).

Study Overview

• Status: Completed
• Conditions: Hypertriglyceridemia; Atherosclerotic Cardiovascular Disease; Severe Hypertriglyceridemia
• Intervention / Treatment: Drug: Olezarsen; Drug: Placebo

Detailed Description

This will be a multi-center, randomized, double-blind, placebo-controlled study in approximately 152 participants with hypertriglyceridemia (triglycerides > 150 milligrams per deciliter [mg/dL]) and established or at increased risk for atherosclerotic cardiovascular disease, and/or with severe hypertriglyceridemia. The study will have an up to 8-week screening period, a 53-week treatment period, and a 13-week post-treatment follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4W2
    • Clinique des Maladies Lipidiques de Quebec Inc.
  • Ontario
    • Sarnia, Ontario, Canada, N7t 4X3
      • Bluewater Clinical Research Group Inc
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
• United States
  • California
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Montclair, California, United States, 91763
      • Catalina Research Institute, LLC
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials, LLC
    • Miami, Florida, United States, 33184
      • De La Cruz Research Center
    • New Port Richey, Florida, United States, 34652
      • Suncoast Clinical Research, Inc.
    • Winter Park, Florida, United States, 32792
      • Research Physicians Network Alliance
  • Georgia
    • Columbus, Georgia, United States, 31904
      • IACT Health
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Evanston Premier Healthcare Research
    • Gurnee, Illinois, United States, 60031
      • Clinical Investigation Specialist
  • Iowa
    • Council Bluffs, Iowa, United States, 51501
      • West Broadway Clinic
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • Louisville Metabolic and Atherosclerosis Research Center (L-MARC)
  • Michigan
    • Flint, Michigan, United States, 48504
      • Aa Mrc, Llc
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Palm Research Center, Inc.
    • Las Vegas, Nevada, United States, 89121
      • Clinical Research of South Nevada
  • Pennsylvania
    • Lansdale, Pennsylvania, United States, 19446
      • Green and Seidner Family Practice Associates
  • South Carolina
    • Little River, South Carolina, United States, 29566
      • Main Street Physicians Care Waterway
  • South Dakota
    • Rapid City, South Dakota, United States, 57702
      • Health Concepts
  • Tennessee
    • Tullahoma, Tennessee, United States, 37388
      • Tennessee Center For Clinical Trials
  • Texas
    • Mesquite, Texas, United States, 75149
      • Southern Endocrinology Associates
  • Virginia
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center
    • Norfolk, Virginia, United States, 23504
      • York Clinical Research LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged ≥ 18 years at the time of informed consent

2. Fall into at least 1 of the following groups (a or b):

   1. Hypertriglyceridemia with fasting TG ≥ 150 mg/dL (1.69 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
   2. Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L).
3. Participants must be on standard-of-care (SOC), lipid-lowering medications per local guidelines.
4. Participants must be willing to comply with diet and lifestyle recommendations as able.

Exclusion Criteria:

1. Diabetes with any of the following:

   1. Newly diagnosed within 12 weeks of screening
   2. Hemoglobin A1C (HbA1c) ≥ 9.5% at Screening
   3. Change in basal insulin regimen > 20% within 3 months prior to Screening
   4. For participants with type 1 diabetes: episode of diabetic ketoacidosis, or ≥ 3 episodes of severe hypoglycemia within 6 months prior to Screening
2. Acute coronary syndrome or stroke/transient ischemic attack (TIA) within 6 months prior to Screening
3. Major surgery, peripheral revascularization, or non-urgent percutaneous coronary intervention (PCI) within 3 months prior to Screening, or upcoming planned major surgery or major procedure (e.g., arterial revascularization) during the course of the study
4. Active pancreatitis within 4 weeks prior to Screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Olezarsen; Olezarsen will be administered once every 4 weeks by subcutaneous (SC) injection for up to 49 weeks.	Drug: Olezarsen; Olezarsen will be administered by SC injection.; Other Names: ISIS 678354; AKCEA-APOCIII-LRx
Placebo Comparator: Placebo; Olezarsen-matching placebo will be administered once every 4 weeks by SC injection for up to 49 weeks.	Drug: Placebo; Olezarsen-matching placebo will be administered once every 4 weeks by SC injection for up to 49 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline at Month 6 (average of Weeks 25 and 27) in Fasting Triglycerides (TG)	Baseline and Month 6

Secondary Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline at Month 12 in Fasting TG	Baseline and Month 12
Proportion of Participants with Baseline TG < 500 mg/dL (5.65 mmol/L) Who Achieve Fasting TG < 150 milligrams per deciliter (mg/dL) (1.69 millimoles per liter [mmol/L]) at Month 6	Baseline and Month 6
Proportion of Participants with Baseline TG < 500 mg/dL (5.65 mmol/L) Who Achieve Fasting TG < 150 mg/dL (1.69 mmol/L) at Month 12	Baseline and Month 12
Proportion of Participants with Baseline TG ≥ 500 mg/dL Who Achieve Fasting TG < 500 mg/dL (5.65 mmol/L) at Month 6	Baseline and Month 6
Proportion of Participants with Baseline TG ≥ 500 mg/dL Who Achieve Fasting TG < 500 mg/dL at Month 12	Baseline and Month 12
Percent Change From Baseline at Months 6 and 12 in Fasting apoC-III	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting VLDL-C	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting Remnant Cholesterol	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting Non-HDL-C	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting HDL-C	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting TC	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting apoB	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in Fasting LDL-C	Baseline, Months 6 and 12
Percent Change From Baseline at Months 6 and 12 in apoA-1	Baseline, Months 6 and 12
Adjudicated acute pancreatitis event rate during the Treatment Period compared to placebo in patients with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment.	Baseline through Month 12
Adjudicated acute pancreatitis event rate during the Treatment Period compared to placebo.	Baseline through Month 12

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2022
• Primary Completion (Actual): March 22, 2023
• Study Completion (Actual): December 21, 2023

Study Registration Dates

• First Submitted: April 26, 2022
• First Submitted That Met QC Criteria: April 26, 2022
• First Posted (Actual): May 2, 2022

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Cardiovascular Diseases; Atherosclerosis; Hypertriglyceridemia
• Other Study ID Numbers: ISIS 678354-CS8

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No