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Completed

NCT Number: NCT03070782

Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease

This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lipoprotein(a) [Lp(a)] levels in participants with hyperlipoproteinemia(a) and established cardiovascular disease (CVD).

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Key information

Conditions

Elevated Lipoprotein(a) Cardiovascular Disease Cardiovascular Diseases Dyslipidemias Hyperlipidemias Hyperlipoproteinemias Lipid Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Clinical Site, Chicoutimi, Quebec, 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
  • Lp(a) plasma level ≥ 60 mg/dL
  • Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors

Key Exclusion Criteria:

  • Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/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

Treatment and study plan

ISIS 681257

Drug

ISIS 681257 solution for SC injection.

Other names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Placebo

Drug

Sterile normal saline (0.9% NaCl)

Primary outcomes

  1. Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

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

    An ANCOVA model was performed on the log ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) 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 Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline - 1) × 100.

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

    Time frame: Up to 16 weeks post treatment period (up to approximately 1.3 years)

    An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study.

  3. Number of Participants With TEAEs by Maximum Severity

    Time frame: Up to 16 weeks post treatment period (up to approximately 1.3 years)

    An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. The severity of TEAEs was assessed based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. TEAEs were graded on a 5-point scale where 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Potentially life-threatening and 5 = Death.

  4. Number of Participants With TEAEs Leading to Study Discontinuation

    Time frame: Up to 16 weeks post treatment period (up to approximately 1.3 years)

    An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAE was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study.

Secondary outcomes

  1. Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

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

    An ANCOVA model was performed on the log ratio of LDL-C value at the Primary Analysis Time Point to LDL-C 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 LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline - 1) × 100.

  2. Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

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

    The percentage of participants who achieved ≤ 125 nmol/L or ≤ 50 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate.

  3. Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL

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

    The percentage of participants who achieved ≤ 75 nmol/L or ≤ 30 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate.

  4. Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

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

    An ANCOVA model was performed on the log ratio of apoB value at the Primary Analysis Time Point to apoB 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 apoB value at the Primary Analysis Time Point to apoB value at Baseline - 1) × 100.

  5. Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

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

    An ANCOVA model was performed on the log ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) 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 OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline - 1) × 100.

  6. Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

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

    An ANCOVA model was performed on the log ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB 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 OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline - 1) × 100.

Other outcomes

  1. To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.

    Time frame: 6 months

    Cmax will be calculated for the treatment groups.

  2. To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.

    Time frame: 6 months

    Tmax will be calculated for the treatment groups.

  3. To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens.

    Time frame: 6 months

    AUC values will be calculated for the treatment groups.

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 681257 (AKCEA-APO(a)-LRx) Administered Subcutaneously to Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

Important dates

Study start
2017
Primary completion
2018
Study completion
2018
First posted
Mar 6, 2017
Registry last updated
Oct 30, 2020

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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