Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Partic... | NCT03070782 | Trialant
NCT03070782
Sponsor
Akcea Therapeutics
Status
Completed
Last Update Posted
Oct 30, 2020Actual
Enrollment
286Actual
Phase
Phase 2
Conditions
Elevated Lipoprotein(a)
Cardiovascular Disease
Interventions
ISIS 681257
Placebo
Countries
United States
Canada
Denmark
Germany
Netherlands
Protocol Section
Identification Module
NCT ID
NCT03070782
Obsolete or Duplicate NCT IDs
Not provided
Organization Study
ISIS 681257-CS6
Secondary IDs
ID
Type
Description
Link
2016-003373-18
EudraCT Number
Brief Title
Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease
Official 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)
Acronym
Not provided
Organization
Akcea TherapeuticsINDUSTRY
Status Module
Record Verification Date
Oct 2020
Overall Recruitment Status or Expanded Access Status
Completed
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Not provided
Expanded Access Info
No
Start Date
Mar 7, 2017Actual
Primary Completion Date
Jul 26, 2018Actual
Completion Date
Nov 13, 2018Actual
First Submitted Date
Jan 31, 2017
First Submission Date that Met QC Criteria
Feb 28, 2017
First Posted Date
Mar 6, 2017Actual
Results Waived
Not provided
Results First Submitted Date
Sep 30, 2020
Results First Submitted that Met QC Criteria
Oct 26, 2020
Results First Posted Date
Oct 30, 2020Actual
Certification/Extension (aka Delayed Results) First Submitted Date
Not provided
Certification/Extension First Submitted that Passed QC Review
Not provided
Certification/Extension First Posted Date
Not provided
Last Update Submitted Date
Oct 26, 2020
Last Update Posted Date
Oct 30, 2020Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Sponsor
Lead Sponsor
Akcea TherapeuticsINDUSTRY
Collaborators
Name
Class
Ionis Pharmaceuticals, Inc.
INDUSTRY
Oversight Module
Has Data Monitoring Committee (DMC)
Yes
Is FDA Regulated Drug
Yes
Is FDA Regulated Device
No
Is Unapproved Device
Not provided
Pediatric Postmarket Surveillance of a Device Product
Not provided
Product Exported from US
Not provided
FDAAA801 Violation
Not provided
Description Module
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 provided
Conditions Module
Conditions
Elevated Lipoprotein(a)
Cardiovascular Disease
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
Design Module
Study Type
Interventional
Number of References to an Expanded Access Study
Not provided
Expanded Access Types
Not provided
Patient Registry
Not provided
Target Follow-Up Duration
Not provided
Phases
Phase 2
Interventional Study Design
Allocation
Biospecimen
No data available
No data is available for this block.
Enrollment
286Actual
Arms/Interventions Module
Arm Groups
Label
Type
Description
Intervention Names
Cohort A: ISIS 681257: 20 mg Q4W
Experimental
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.
Drug: ISIS 681257
Cohort B: ISIS 681257: 40 mg Q4W
Experimental
Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
Drug: ISIS 681257
Cohort C: ISIS 681257: 60 mg Q4W
Experimental
Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
Drug: ISIS 681257
Cohort D: ISIS 681257: 20 mg Q2W
Experimental
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.
Drug: ISIS 681257
Cohort E: ISIS 681257: 20 mg QW
Experimental
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.
Interventions
Name
Type
Description
Arm Group Labels
Other Names
ISIS 681257
Drug
ISIS 681257 solution for SC injection.
Cohort A: ISIS 681257: 20 mg Q4W
Cohort B: ISIS 681257: 40 mg Q4W
Cohort C: ISIS 681257: 60 mg Q4W
Outcomes Module
Primary Outcomes
Measure
Description
Time Frame
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.
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
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.
Up to 16 weeks post treatment period (up to approximately 1.3 years)
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.
Up to 16 weeks post treatment period (up to approximately 1.3 years)
Secondary Outcomes
Measure
Description
Time Frame
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.
Other Outcomes
Measure
Description
Time Frame
To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.
Cmax will be calculated for the treatment groups.
6 months
To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.
Eligibility Module
Eligibility 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
Tekendo-Ngongang C, Gleeson JG, Mignon L. Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases. J Am Soc Nephrol. 2024 Dec 1;35(12):1774-1777. doi: 10.1681/ASN.0000000532. Epub 2024 Sep 27. No abstract available.
Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, Kroon J, Schnitzler JG, Dzobo KE, Cupido AJ, Tsimikas S, Stroes ESG, de Winther MPJ, Bahjat M. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur Heart J. 2020 Jun 21;41(24):2262-2271. doi: 10.1093/eurheartj/ehaa171.
See Also Links
Not provided
Available IPD Information
Not provided
IPD Sharing Statement Module
Plan to Share IPD
No
Description
Not provided
Types
Not provided
Time Frame
Not provided
Access Criteria
Not provided
URL
Not provided
Results Section
Participant Flow Module
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.
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.
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
FG000
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.
FG001
Cohort B: ISIS 681257: 40 mg Q4W
Periods
Title
Milestones
Reasons Not Completed
Overall Study
Type
Comment
Milestone Data
STARTED
Baseline Characteristics Module
Baseline Analysis Population Description
Outcome Measures Module
Outcome Measures
Adverse Events Module
Frequency Threshold
5
More Info Module
Limitations and Caveats
Not provided
Annotation Section
No data available
No data is available for this block.
Document Section
Large Document Module
Document Has No Statistical Analysis Plan (SAP)
Not provided
Uploaded Document Information
Type
Includes Protocol
Includes SAP
Includes ICF
Document Label
Document Date
Document Uploaded Date
Document File Name
Prot
Yes
No
No
Study Protocol
Jan 25, 2018
Sep 30, 2020
Derived Section
Miscellaneous Info Module
Version Holder
Jul 10, 2026
Removed Countries
Not provided
Submission Tracking
Estimated Results First Submitted Date
Not provided
Condition Browse Module
MeSH Terms
Intervention Browse Module
MeSH Terms
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Not provided
Primary Purpose
Treatment
Observational Model
Not provided
Time Perspective
Not provided
Masking Info
Masking
Triple
Masking Description
Not provided
Who Masked
ParticipantInvestigatorOutcomes Assessor
Drug: ISIS 681257
Placebo
Placebo Comparator
Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Drug: Placebo
Cohort D: ISIS 681257: 20 mg Q2W
Cohort E: ISIS 681257: 20 mg QW
AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
Placebo
Drug
Sterile normal saline (0.9% NaCl)
Placebo
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.
Up to 16 weeks post treatment period (up to approximately 1.3 years)
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)
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.
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
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.
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)
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.
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)]
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.
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)
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.
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Tmax will be calculated for the treatment groups.
6 months
To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens.
AUC values will be calculated for the treatment groups.
Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1.
Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
FG002
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.
FG003
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.
FG004
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.
FG005
Placebo
Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
FG00048 subjects
FG00148 subjects
FG00247 subjects
FG00348 subjects
FG00448 subjects
FG00547 subjects
COMPLETED
Completed here refers to participants who completed study treatment.
FG00041 subjects
FG00147 subjects
FG00243 subjects
FG00343 subjects
FG00436 subjects
FG00540 subjects
NOT COMPLETED
FG0007 subjects
FG0011 subjects
FG0024 subjects
FG0035 subjects
FG00412 subjects
FG0057 subjects
Type
Comment
Reasons
Adverse Event
FG0003 subjects
FG0010 subjects
FG0023 subjects
FG0031 subjects
FG0046 subjects
FG0052 subjects
Withdrawal by Subject
FG0002 subjects
FG0011 subjects
FG0021 subjects
FG0030 subjects
FG004
Reason Not Specified
FG0002 subjects
FG0010 subjects
FG0020 subjects
FG0031 subjects
FG004
Ineligibility
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0031 subjects
FG004
Pregnancy
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0031 subjects
FG004
Investigator Judgement
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0031 subjects
FG004
Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
BG000
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.
BG001
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.
BG002
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.
BG003
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.
BG004
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.
BG005
Placebo
Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
BG006
Total
Total of all reporting groups
Denominators
Units
Counts
Participants
BG00048
BG00148
BG00247
BG00348
BG00448
BG00547
BG006286
Baseline Measures
Title
Description
Population Description
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Denominator Units Selected
Denominators
Classes
Age, Continuous
Mean
Full Range
years
Title
Denominators
Categories
Title
Measurements
BG00060.0(38 to 77)
BG00161.3(39 to 80)
BG00262.2(40 to 79)
BG003
Sex: Female, Male
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Female
BG00019
BG00112
BG002
Ethnicity (NIH/OMB)
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Hispanic or Latino
BG0002
BG0011
BG002
Race (NIH/OMB)
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
American Indian or Alaska Native
BG0000
BG0010
BG002
Type
Title
Description
Population Description
Reporting Status
Anticipated Posting Date
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Time Frame
Units Analyzed
Denominator Units Selected
Arm/Group Information
Denominators
Classes
Analyses
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.
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.
Posted
Geometric Mean
95% Confidence Interval
percent change
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
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.
OG003
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.
OG004
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.
OG005
Placebo
Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Units
Counts
Participants
OG00048
OG00148
OG00247
OG003
Title
Denominators
Categories
Title
Measurements
OG000-35(-45 to -22)
OG001-56(-63 to -48)
OG002-72(-76 to -67)
OG003
Group IDs
Group Description
Statistical Method
Statistical Comment
P-Value
P-Value Comment
Parameter Type
Parameter Value
Dispersion Type
Dispersion Value
Confidence Interval Sides
Confidence Interval %
CI Lower Limit
CI Upper Limit
CI Lower Limit Comment
CI Upper Limit Comment
Estimate Comment
Tested Non-Inferiority
Non-Inferiority Type
Non-Inferiority Comment
Other Analysis Description
OG000
OG005
ANCOVA
0.0032
Mean Difference in % CFB
-31
2-Sided
95
-46
-12
Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
Superiority
OG001
OG005
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.
Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
Posted
Count of Participants
Participants
Up to 16 weeks post treatment period (up to approximately 1.3 years)
ID
Title
Description
OG000
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.
OG001
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.
OG002
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.
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.
Posted
Count of Participants
Participants
Up to 16 weeks post treatment period (up to approximately 1.3 years)
ID
Title
Description
OG000
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.
OG001
Cohort B: ISIS 681257: 40 mg Q4W
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.
Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
Posted
Count of Participants
Participants
Up to 16 weeks post treatment period (up to approximately 1.3 years)
ID
Title
Description
OG000
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.
OG001
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.
OG002
Cohort C: ISIS 681257: 60 mg Q4W
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.
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.
Posted
Geometric Mean
95% Confidence Interval
percent change
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
Cohort C: ISIS 681257: 60 mg Q4W
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.
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.
Posted
Number
percentage of participants
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
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.
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.
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.
Posted
Number
percentage of participants
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
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.
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.
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.
Posted
Geometric Mean
95% Confidence Interval
percent change
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
Cohort C: ISIS 681257: 60 mg Q4W
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.
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.
Posted
Geometric Mean
95% Confidence Interval
percent change
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
Cohort C: ISIS 681257: 60 mg Q4W
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.
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.
Posted
Geometric Mean
95% Confidence Interval
percent change
Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
ID
Title
Description
OG000
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.
OG001
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.
OG002
Cohort C: ISIS 681257: 60 mg Q4W
Other Pre-specified
To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.
Cmax will be calculated for the treatment groups.
Not Posted
6 months
Participants
Other Pre-specified
To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.
Tmax will be calculated for the treatment groups.
Not Posted
6 months
Participants
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.
Not Posted
6 months
Participants
Time Frame
Up to 16 weeks post-treatment period (up to approximately 1.3 years)
Description
Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
All-Cause Mortality Comment
Not provided
Arm/Groups
ID
Title
Description
Deaths (Affected)
Deaths (At Risk)
Serious Events (Affected)
Serious Events (At Risk)
Other Events (Affected)
Other Events (At Risk)
EG000
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.
0
48
7
48
38
48
EG001
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.
0
48
7
48
42
48
EG002
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.
1
47
7
47
40
47
EG003
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.
0
48
3
48
36
48
EG004
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.
1
48
4
48
42
48
EG005
Placebo
Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
0
47
3
47
36
47
Serious Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Acute myocardial infarction
Cardiac disorders
MedDRA Version 20.0
Systematic Assessment
EG0002 affected48 at risk
EG0010 affected48 at risk
EG0021 affected47 at risk
EG0031 affected48 at risk
EG0040 affected48 at risk
EG0050 affected47 at risk
Angina unstable
Cardiac disorders
MedDRA Version 20.0
Systematic Assessment
EG0001 affected48 at risk
EG0010 affected48 at risk
EG0021 affected47 at risk
EG003
Angina pectoris
Cardiac disorders
MedDRA Version 20.0
Systematic Assessment
EG0001 affected48 at risk
EG0011 affected48 at risk
EG0020 affected47 at risk
EG003
Coronary artery disease
Cardiac disorders
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0011 affected48 at risk
EG0020 affected47 at risk
EG003
Ventricular tachycardia
Cardiac disorders
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0021 affected47 at risk
EG003
Ankle fracture
Injury, poisoning and procedural complications
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Joint dislocation
Injury, poisoning and procedural complications
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Lower limb fracture
Injury, poisoning and procedural complications
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0011 affected48 at risk
EG0020 affected47 at risk
EG003
Radius fracture
Injury, poisoning and procedural complications
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0021 affected47 at risk
EG003
Road traffic accident
Injury, poisoning and procedural complications
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0021 affected47 at risk
EG003
Gastrointestinal anastomotic stenosis
Injury, poisoning and procedural complications
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Oesophagitis haemorrhagic
Gastrointestinal disorders
MedDRA Version 20.0
Systematic Assessment
EG0001 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Pancreatitis acute
Gastrointestinal disorders
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Malaise
General disorders
MedDRA Version 20.0
Systematic Assessment
EG0001 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Non-cardiac chest pain
General disorders
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0011 affected48 at risk
EG0020 affected47 at risk
EG003
Cyst
General disorders
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Pneumonia
Infections and infestations
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Upper respiratory tract infection
Infections and infestations
MedDRA Version 20.0
Systematic Assessment
EG0000 affected48 at risk
EG0011 affected48 at risk
EG0020 affected47 at risk
EG003
Lung neoplasm
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA Version 20.0
Systematic Assessment
EG0001 affected48 at risk
EG0010 affected48 at risk
EG0020 affected47 at risk
EG003
Lung neoplasm malignant
Neoplasms benign, malignant and unspecified (incl cysts and polyps)