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

Cardiovascular Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03385239
• Other study ID #: ISIS 678354-CS2
• Status: Completed
• Phase: Phase 2
• Start date: January 30, 2018
• Est. completion date: February 25, 2020

Study information

• Verified date: December 2022
• Source: Akcea Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 114
• Est. completion date: February 25, 2020
• Est. primary completion date: November 25, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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).

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Hypertriglyceridemia

Intervention

Drug:
• ISIS 678354
ISIS 678354 solution for SC injection.
• Placebo
Sterile Normal Saline (0.9% NaCl).

Locations

Country	Name	City	State
Canada	Clinical Site	Brossard	Quebec
Canada	Clinical Site	Cambridge	Ontario
Canada	Clinical Site	Chicoutimi	Quebec
Canada	Clinical Site	Gatineau	Quebec
Canada	Clinical Site	Montréal	Quebec
Canada	Clinical Site	Québec	Quebec
Canada	Clinical Site	Sudbury	Ontario
United States	Clinical Site	Ames	Iowa
United States	Clinical Site	Boca Raton	Florida
United States	Clinical Site	Carmichael	California
United States	Clinical Site	Cooperstown	New York
United States	Clinical Site	Cottonwood	Arizona
United States	Clinical Site	Fall River	Massachusetts
United States	Clinical Site	Fresno	California
United States	Clinical Site	Greer	South Carolina
United States	Clinical Site	High Point	North Carolina
United States	Clinical Site	Houston	Texas
United States	Clinical Site	Jacksonville	Florida
United States	Clinical Site	Kansas City	Kansas
United States	Clinical Site	La Jolla	California
United States	Clinical Site	Lansdale	Pennsylvania
United States	Clinical Site	Little Rock	Arkansas
United States	Clinical Site	Long Beach	California
United States	Clinical Site	Louisville	Kentucky
United States	Clinical Site	Milwaukee	Wisconsin
United States	Clinical Site	Montclair	California
United States	Clinical Site	Munster	Indiana
United States	Clinical Site	New Port Richey	Florida
United States	Clinical Site	Portland	Oregon
United States	Clinical Site	Providence	Rhode Island
United States	Clinical Site	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Akcea Therapeutics	Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)