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

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Hypertriglyceridemia
• Intervention / Treatment: Drug: Placebo; Drug: ISIS 678354

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Cambridge, Ontario, Canada, N1R 6V6
      • Clinical Site
    • Sudbury, Ontario, Canada, P3E 5M4
      • Clinical Site
  • Quebec
    • Brossard, Quebec, Canada, J4Z 2K9
      • Clinical Site
    • Chicoutimi, Quebec, Canada
      • Clinical Site
    • Gatineau, Quebec, Canada, J8Y 6S8
      • Clinical Site
    • Montréal, Quebec, Canada, H1T 1C8
      • Clinical Site
    • Québec, Quebec, Canada, G1V 4W2
      • Clinical Site
• United States
  • Arizona
    • Cottonwood, Arizona, United States, 86326
      • Clinical Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Site
  • California
    • Carmichael, California, United States, 95608
      • Clinical Site
    • Fresno, California, United States, 93720
      • Clinical Site
    • La Jolla, California, United States, 92037-7410
      • Clinical Site
    • Long Beach, California, United States, 90807
      • Clinical Site
    • Montclair, California, United States, 91763
      • Clinical Site
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Clinical Site
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Clinical Site
    • Jacksonville, Florida, United States, 32216
      • Clinical Site
    • New Port Richey, Florida, United States, 34652
      • Clinical Site
  • Indiana
    • Munster, Indiana, United States, 46321
      • Clinical Site
  • Iowa
    • Ames, Iowa, United States, 50010
      • Clinical Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Clinical Site
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • Clinical Site
  • Massachusetts
    • Fall River, Massachusetts, United States, 02721
      • Clinical Site
  • New York
    • Cooperstown, New York, United States, 13326
      • Clinical Site
  • North Carolina
    • High Point, North Carolina, United States, 27262
      • Clinical Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Clinical Site
  • Pennsylvania
    • Lansdale, Pennsylvania, United States, 19446
      • Clinical Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Clinical Site
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Clinical Site
  • Texas
    • Houston, Texas, United States, 77030
      • Clinical Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Clinical Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Akcea Therapeutics
• Collaborators: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O'Dea LSL, Tsimikas S, Gaudet D. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2018
• Primary Completion (Actual): November 25, 2019
• Study Completion (Actual): February 25, 2020

Study Registration Dates

• First Submitted: December 1, 2017
• First Submitted That Met QC Criteria: December 20, 2017
• First Posted (Actual): December 28, 2017

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Dyslipidemia; Vascular Diseases; Hyperlipidemia; AKCEA-APOCIII-LRx; IONIS-APOCIII-LRx; Metabolic Disease; Cardiac Disease; Lipid Metabolism Disorders; Triglycerides High
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Cardiovascular Diseases; Hypertriglyceridemia
• Other Study ID Numbers: ISIS 678354-CS2

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
• product manufactured in and exported from the U.S.: No