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)
Overview
- Phase
- Phase 2
- Intervention
- ISIS 681257
- Conditions
- Elevated Lipoprotein(a)
- Sponsor
- Akcea Therapeutics
- Enrollment
- 286
- Locations
- 1
- Primary Endpoint
- Number of Participants With TEAEs Leading to Study Discontinuation
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
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).
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Cohort A: ISIS 681257: 20 mg Q4W
Cohort A participants received 20 milligrams (mg) ISIS 681257, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses.
Intervention: ISIS 681257
Cohort B: ISIS 681257: 40 mg Q4W
Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
Intervention: ISIS 681257
Cohort C: ISIS 681257: 60 mg Q4W
Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
Intervention: ISIS 681257
Cohort D: ISIS 681257: 20 mg Q2W
Cohort D participants received 20 mg of ISIS 681257, SC injection, once every 2 weeks (Q2W), for up to 51 weeks and a maximum of 26 doses.
Intervention: ISIS 681257
Cohort E: ISIS 681257: 20 mg QW
Cohort E participants received 20 mg of ISIS 681257, SC injection, once weekly (QW), for up to 52 weeks and a maximum of 52 doses.
Intervention: ISIS 681257
Placebo
Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Intervention: Placebo
Outcomes
Primary Outcomes
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.
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.
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.
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.
Secondary Outcomes
- Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)(Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E))
- Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)(Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E))
- Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)(Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E))
- Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL(Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E))
- Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)(Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E))
- Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)](Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E))