Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease
- Conditions
- Elevated Lipoprotein(a)Cardiovascular Disease
- Interventions
- Drug: Placebo
- Registration Number
- NCT03070782
- Lead Sponsor
- Akcea Therapeutics
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 286
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort E: ISIS 681257: 20 mg QW ISIS 681257 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. Placebo Placebo Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257). Cohort A: ISIS 681257: 20 mg Q4W ISIS 681257 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. Cohort B: ISIS 681257: 40 mg Q4W ISIS 681257 Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses. Cohort C: ISIS 681257: 60 mg Q4W ISIS 681257 Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses. Cohort D: ISIS 681257: 20 mg Q2W ISIS 681257 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.
- Primary Outcome Measures
Name Time Method Number of Participants With TEAEs Leading to Study Discontinuation 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 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) 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 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 Outcome Measures
Name Time Method 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) 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.
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) 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.
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) 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.
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) 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.
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) 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.
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) 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.
Trial Locations
- Locations (1)
Clinical Site
🇳🇱Amsterdam, Netherlands