Cardiovascular Disease, Elevated Lipoprotein(a)
Conditions
Keywords
IONIS-APO(a)-LRx, AKCEA-APO(a)-LRx, Dyslipidemia, Dyslipoproteinemia, Hyperlipidemia, Hyperlipoproteinemia, Hyperlipoproteinemia(a), Hyperlipoproteinemia a, Lipoprotein, Lipoprotein(a), Lipoprotein a, Lp(a), Lp a
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).
Interventions
DRUGISIS 681257
ISIS 681257 solution for SC injection.
DRUGPlacebo
Sterile normal saline (0.9% NaCl)
Sponsors
Ionis Pharmaceuticals, Inc.
Akcea Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens. | 6 months | Cmax will be calculated for the treatment groups. |
| To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens. | 6 months | AUC values will be calculated for the treatment groups. |
| To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens. | 6 months | Tmax will be calculated for the treatment groups. |
Countries
Canada, Denmark, Germany, Netherlands, United States
Participant flow
Recruitment details
Participants with a clinical diagnosis of hyperlipoproteinemia(a) and established CVD were enrolled in 31 study centers in United States, Canada, Denmark, Germany and Netherlands between 7th March 2017 to 13th November 2018.
Pre-assignment details
286 participants were randomized in a 1:1:1:1:1 ratio to Cohorts A, B, C, D or E. In each cohort, participants were randomized in a 5:1 ratio to receive ISIS 681257 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 48 |
| 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. | 48 |
| 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. | 47 |
| 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. | 48 |
| 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. | 48 |
| Placebo Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257). | 47 |
| Total | 286 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 3 | 1 | 6 | 2 |
| Overall Study | Ineligibility | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Investigator Judgement | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Reason Not Specified | 2 | 0 | 0 | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 0 | 4 | 3 |
Baseline characteristics
| Characteristic | Cohort A: ISIS 681257: 20 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort E: ISIS 681257: 20 mg QW | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.0 years | 57.9 years | 61.3 years | 62.2 years | 58.9 years | 59.9 years | 60.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 48 Participants | 47 Participants | 47 Participants | 47 Participants | 46 Participants | 281 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 44 Participants | 47 Participants | 45 Participants | 47 Participants | 47 Participants | 46 Participants | 276 Participants |
| Sex: Female, Male Female | 19 Participants | 17 Participants | 12 Participants | 14 Participants | 20 Participants | 15 Participants | 97 Participants |
| Sex: Female, Male Male | 29 Participants | 31 Participants | 36 Participants | 33 Participants | 28 Participants | 32 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 48 | 1 / 47 | 0 / 48 | 1 / 48 | 0 / 47 |
| other Total, other adverse events | 38 / 48 | 42 / 48 | 40 / 47 | 36 / 48 | 42 / 48 | 36 / 47 |
| serious Total, serious adverse events | 7 / 48 | 7 / 48 | 7 / 47 | 3 / 48 | 4 / 48 | 3 / 47 |
Outcome results
Primary
Number of Participants With TEAEs by Maximum Severity
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.
Time frame: Up to 16 weeks post treatment period (up to approximately 1.3 years)
Population: Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). Only participants with at least one TEAE were analyzed for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Moderate | 20 Participants |
| Cohort A: ISIS 681257: 20 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Mild | 20 Participants |
| Cohort A: ISIS 681257: 20 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Severe | 6 Participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Moderate | 19 Participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Mild | 21 Participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Severe | 3 Participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Moderate | 21 Participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Mild | 16 Participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Number of Participants With TEAEs by Maximum Severity | Severe | 6 Participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Number of Participants With TEAEs by Maximum Severity | Moderate | 15 Participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Number of Participants With TEAEs by Maximum Severity | Mild | 24 Participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Number of Participants With TEAEs by Maximum Severity | Severe | 2 Participants |
| Cohort E: ISIS 681257: 20 mg QW | Number of Participants With TEAEs by Maximum Severity | Moderate | 20 Participants |
| Cohort E: ISIS 681257: 20 mg QW | Number of Participants With TEAEs by Maximum Severity | Mild | 21 Participants |
| Cohort E: ISIS 681257: 20 mg QW | Number of Participants With TEAEs by Maximum Severity | Severe | 3 Participants |
| Placebo | Number of Participants With TEAEs by Maximum Severity | Mild | 22 Participants |
| Placebo | Number of Participants With TEAEs by Maximum Severity | Severe | 3 Participants |
| Placebo | Number of Participants With TEAEs by Maximum Severity | Moderate | 16 Participants |
Primary
Number of Participants With TEAEs Leading to Study Discontinuation
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.
Time frame: Up to 16 weeks post treatment period (up to approximately 1.3 years)
Population: Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Number of Participants With TEAEs Leading to Study Discontinuation | 3 Participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Number of Participants With TEAEs Leading to Study Discontinuation | 0 Participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Number of Participants With TEAEs Leading to Study Discontinuation | 3 Participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Number of Participants With TEAEs Leading to Study Discontinuation | 1 Participants |
| Cohort E: ISIS 681257: 20 mg QW | Number of Participants With TEAEs Leading to Study Discontinuation | 6 Participants |
| Placebo | Number of Participants With TEAEs Leading to Study Discontinuation | 2 Participants |
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), 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.
Time frame: Up to 16 weeks post treatment period (up to approximately 1.3 years)
Population: Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 46 Participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 43 Participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 43 Participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 41 Participants |
| Cohort E: ISIS 681257: 20 mg QW | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 44 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 41 Participants |
Primary
Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible intent-to-treat (ITT) population as delineated in ICH Guideline E9.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | -35 percent change |
| Cohort B: ISIS 681257: 40 mg Q4W | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | -56 percent change |
| Cohort C: ISIS 681257: 60 mg Q4W | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | -72 percent change |
| Cohort D: ISIS 681257: 20 mg Q2W | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | -58 percent change |
| Cohort E: ISIS 681257: 20 mg QW | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | -80 percent change |
| Placebo | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | -6 percent change |
p-value: 0.003295% CI: [-46, -12]ANCOVA
p-value: <0.000195% CI: [-64, -41]ANCOVA
p-value: <0.000195% CI: [-77, -62]ANCOVA
p-value: <0.000195% CI: [-65, -43]ANCOVA
p-value: <0.000195% CI: [-83, -72]ANCOVA
Secondary
Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | 22.9 percentage of participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | 62.5 percentage of participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | 80.9 percentage of participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | 64.6 percentage of participants |
| Cohort E: ISIS 681257: 20 mg QW | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | 97.9 percentage of participants |
| Placebo | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | 6.4 percentage of participants |
p-value: 0.028695% CI: [1.2, 21]Regression, Logistic
p-value: <0.000195% CI: [7.3, 131.4]Regression, Logistic
p-value: <0.000195% CI: [24, 627.4]Regression, Logistic
p-value: <0.000195% CI: [9.8, 195]Regression, Logistic
p-value: <0.000195% CI: [109.3, 11571]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | 6.3 percentage of participants |
| Cohort B: ISIS 681257: 40 mg Q4W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | 25.0 percentage of participants |
| Cohort C: ISIS 681257: 60 mg Q4W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | 53.2 percentage of participants |
| Cohort D: ISIS 681257: 20 mg Q2W | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | 33.3 percentage of participants |
| Cohort E: ISIS 681257: 20 mg QW | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | 70.8 percentage of participants |
| Placebo | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | 0 percentage of participants |
p-value: 0.200795% CI: [0.3, 155.3]Regression, Logistic
p-value: 0.025895% CI: [1.5, 521.5]Regression, Logistic
p-value: 0.001495% CI: [6.2, 2098.5]Regression, Logistic
p-value: 0.006395% CI: [3.2, 1128]Regression, Logistic
p-value: <0.000195% CI: [18.3, 6597.9]Regression, Logistic
Secondary
Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | -7 percent change |
| Cohort B: ISIS 681257: 40 mg Q4W | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | -26 percent change |
| Cohort C: ISIS 681257: 60 mg Q4W | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | -16 percent change |
| Cohort D: ISIS 681257: 20 mg Q2W | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | -17 percent change |
| Cohort E: ISIS 681257: 20 mg QW | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | -23 percent change |
| Placebo | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | -1 percent change |
p-value: 0.440795% CI: [-19, 9]ANCOVA
p-value: <0.000195% CI: [-35, -13]ANCOVA
p-value: 0.036895% CI: [-26, -1]ANCOVA
p-value: 0.021695% CI: [-28, -3]ANCOVA
p-value: 0.001295% CI: [-33, -9]ANCOVA
Secondary
Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | -3 percent change |
| Cohort B: ISIS 681257: 40 mg Q4W | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | -15 percent change |
| Cohort C: ISIS 681257: 60 mg Q4W | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | -8 percent change |
| Cohort D: ISIS 681257: 20 mg Q2W | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | -9 percent change |
| Cohort E: ISIS 681257: 20 mg QW | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | -16 percent change |
| Placebo | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | 1 percent change |
p-value: 0.402295% CI: [-12, 5]ANCOVA
p-value: <0.000195% CI: [-23, -9]ANCOVA
p-value: 0.032395% CI: [-17, -1]ANCOVA
p-value: 0.015795% CI: [-18, -2]ANCOVA
p-value: <0.000195% CI: [-24, -9]ANCOVA
Secondary
Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | -28 percent change |
| Cohort B: ISIS 681257: 40 mg Q4W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | -49 percent change |
| Cohort C: ISIS 681257: 60 mg Q4W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | -63 percent change |
| Cohort D: ISIS 681257: 20 mg Q2W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | -45 percent change |
| Cohort E: ISIS 681257: 20 mg QW | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | -70 percent change |
| Placebo | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | -20 percent change |
p-value: 0.495695% CI: [-32, 21]ANCOVA
p-value: 0.002795% CI: [-52, -14]ANCOVA
p-value: <0.000195% CI: [-65, -38]ANCOVA
p-value: 0.011495% CI: [-48, -8]ANCOVA
p-value: <0.000195% CI: [-72, -49]ANCOVA
Secondary
Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)
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.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A: ISIS 681257: 20 mg Q4W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | -37 percent change |
| Cohort B: ISIS 681257: 40 mg Q4W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | -57 percent change |
| Cohort C: ISIS 681257: 60 mg Q4W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | -79 percent change |
| Cohort D: ISIS 681257: 20 mg Q2W | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | -64 percent change |
| Cohort E: ISIS 681257: 20 mg QW | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | -88 percent change |
| Placebo | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | 14 percent change |
p-value: 0.00295% CI: [-62, -19]ANCOVA
p-value: <0.000195% CI: [-74, -46]ANCOVA
p-value: <0.000195% CI: [-87, -73]ANCOVA
p-value: <0.000195% CI: [-78, -54]ANCOVA
p-value: <0.000195% CI: [-93, -84]ANCOVA
Other Pre-specified
To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens.
AUC values will be calculated for the treatment groups.
Time frame: 6 months
Other Pre-specified
To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.
Cmax will be calculated for the treatment groups.
Time frame: 6 months
Other Pre-specified
To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.
Tmax will be calculated for the treatment groups.
Time frame: 6 months