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Completed

NCT Number: NCT03385239

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

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Key information

Conditions

Hypertriglyceridemia Cardiovascular Diseases Dyslipidemias Heart Diseases Hyperlipidemias Lipid Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases Vascular Diseases

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Clinical Site, Cambridge, Ontario, Canada

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

ISIS 678354

Drug

ISIS 678354 solution for SC injection.

Other names: AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx

Placebo

Drug

Sterile Normal Saline (0.9% NaCl).

Primary outcomes

  1. Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point

    Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

    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.

  2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

    Time frame: Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)

    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.

Secondary outcomes

  1. 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

    Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

    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.

  2. Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])

    Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

    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.

  3. Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)

    Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)

    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.

  4. Maximum Plasma Concentration (Cmax) of ISIS 678354

    Time frame: 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)

  5. Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354

    Time frame: 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)

  6. Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354

    Time frame: 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)

Sponsors and collaborators

Lead sponsor

Akcea Therapeutics

Industry

Collaborators

  • Ionis Pharmaceuticals, Inc.

Registry information

Official study 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

Important dates

Study start
2018
Primary completion
2019
Study completion
2020
First posted
Dec 28, 2017
Registry last updated
Jan 11, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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