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

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ClinicalTrials.gov Identifier: NCT03070782

Recruitment Status : Completed

First Posted : March 6, 2017

Results First Posted : October 30, 2020

Last Update Posted : October 30, 2020

Sponsor:

Collaborator:

Ionis Pharmaceuticals, Inc.

Information provided by (Responsible Party):

Akcea Therapeutics

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions	Elevated Lipoprotein(a) Cardiovascular Disease
Interventions	Drug: ISIS 681257 Drug: Placebo
Enrollment	286

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.


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Period Title: Overall Study
Started	48	48	47	48	48	47
Completed ^[1]	41	47	43	43	36	40
Not Completed	7	1	4	5	12	7
Reason Not Completed
Adverse Event	3	0	3	1	6	2
Withdrawal by Subject	2	1	1	0	4	3
Reason Not Specified	2	0	0	1	2	1
Ineligibility	0	0	0	1	0	1
Pregnancy	0	0	0	1	0	0
Investigator Judgement	0	0	0	1	0	0
[1] Completed here refers to participants who completed study treatment.

Baseline Characteristics

Arm/Group Title		Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo	Total
Arm/Group Description		Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...	Total of all reporting groups
Arm/Group Description		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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).	Total of all reporting groups
Overall Number of Baseline Participants		48	48	47	48	48	47	286
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).
Age, Continuous Mean (Full Range) Unit of measure: Years
	Number Analyzed	48 participants	48 participants	47 participants	48 participants	48 participants	47 participants	286 participants
		60.0 (38 to 77)	61.3 (39 to 80)	62.2 (40 to 79)	57.9 (30 to 76)	58.9 (40 to 75)	59.9 (34 to 76)	60.0 (30 to 80)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	48 participants	48 participants	47 participants	48 participants	48 participants	47 participants	286 participants
	Female	19 39.6%	12 25.0%	14 29.8%	17 35.4%	20 41.7%	15 31.9%	97 33.9%
	Male	29 60.4%	36 75.0%	33 70.2%	31 64.6%	28 58.3%	32 68.1%	189 66.1%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	48 participants	48 participants	47 participants	48 participants	48 participants	47 participants	286 participants
	Hispanic or Latino	2 4.2%	1 2.1%	0 0.0%	0 0.0%	1 2.1%	1 2.1%	5 1.7%
	Not Hispanic or Latino	46 95.8%	47 97.9%	47 100.0%	48 100.0%	47 97.9%	46 97.9%	281 98.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	48 participants	48 participants	47 participants	48 participants	48 participants	47 participants	286 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	1 2.1%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 2.1%	2 0.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 4.2%	3 6.3%	0 0.0%	0 0.0%	1 2.1%	0 0.0%	6 2.1%
	White	44 91.7%	45 93.8%	47 100.0%	47 97.9%	47 97.9%	46 97.9%	276 96.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	1 2.1%	0 0.0%	0 0.0%	1 2.1%	0 0.0%	0 0.0%	2 0.7%

Outcome Measures

1.Primary Outcome


Title	Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point
Description	An ANCOVA model was performed on the log ratio of Lp(a) value at the P...
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Geometric Mean (95% Confidence Interval) Unit of Measure: percent change
	-35 (-45 to -22)	-56 (-63 to -48)	-72 (-76 to -67)	-58 (-65 to -50)	-80 (-83 to -76)	-6 (-21 to 12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0032
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-31
	Confidence Interval	(2-Sided) 95% -46 to -12
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-54
	Confidence Interval	(2-Sided) 95% -64 to -41
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-70
	Confidence Interval	(2-Sided) 95% -77 to -62
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-56
	Confidence Interval	(2-Sided) 95% -65 to -43
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-78
	Confidence Interval	(2-Sided) 95% -83 to -72
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

2.Primary Outcome


Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	An adverse event (AE) was defined as any unfavorable and unintended si...
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Measure Type: Count of Participants Unit of Measure: Participants
	46 95.8%	43 89.6%	43 91.5%	41 85.4%	44 91.7%	41 87.2%

3.Primary Outcome


Title	Number of Participants With TEAEs by Maximum Severity
Description	An AE was defined as any unfavorable and unintended sign (including a ...
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	46	43	43	41	44	41
Measure Type: Count of Participants Unit of Measure: Participants
Mild	20 43.5%	21 48.8%	16 37.2%	24 58.5%	21 47.7%	22 53.7%
Moderate	20 43.5%	19 44.2%	21 48.8%	15 36.6%	20 45.5%	16 39.0%
Severe	6 13.0%	3 7.0%	6 14.0%	2 4.9%	3 6.8%	3 7.3%

4.Primary Outcome


Title	Number of Participants With TEAEs Leading to Study Discontinuation
Description	An AE was defined as any unfavorable and unintended sign (including a ...
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Measure Type: Count of Participants Unit of Measure: Participants
	3 6.3%	0 0.0%	3 6.4%	1 2.1%	6 12.5%	2 4.3%

5.Secondary Outcome


Title	Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)
Description	An ANCOVA model was performed on the log ratio of LDL-C value at the P...
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Geometric Mean (95% Confidence Interval) Unit of Measure: percent change
	-7 (-16 to 3)	-26 (-33 to -18)	-16 (-24 to -7)	-17 (-25 to -8)	-23 (-31 to -14)	-1 (-11 to 9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4407
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-6
	Confidence Interval	(2-Sided) 95% -19 to 9
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-25
	Confidence Interval	(2-Sided) 95% -35 to -13
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0368
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-14
	Confidence Interval	(2-Sided) 95% -26 to -1
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0216
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-16
	Confidence Interval	(2-Sided) 95% -28 to -3
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0012
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-22
	Confidence Interval	(2-Sided) 95% -33 to -9
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

6.Secondary Outcome


Title	Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)
Description	The percentage of participants who achieved ≤ 125 nmol/L or X...
Description	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)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Measure Type: Number Unit of Measure: percentage of participants
	22.9	62.5	80.9	64.6	97.9	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0286
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.98
	Confidence Interval	(2-Sided) 95% 1.2 to 21.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	31.07
	Confidence Interval	(2-Sided) 95% 7.3 to 131.4
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	122.81
	Confidence Interval	(2-Sided) 95% 24.0 to 627.4
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	43.78
	Confidence Interval	(2-Sided) 95% 9.8 to 195.0
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1124.56
	Confidence Interval	(2-Sided) 95% 109.3 to 11571
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL
Description	The percentage of participants who achieved ≤ 75 nmol/L or Ͱ...
Description	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)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Measure Type: Number Unit of Measure: percentage of participants
	6.3	25.0	53.2	33.3	70.8	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2007
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.34
	Confidence Interval	(2-Sided) 95% 0.3 to 155.3
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0258
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	27.92
	Confidence Interval	(2-Sided) 95% 1.5 to 521.5
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0014
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	113.92
	Confidence Interval	(2-Sided) 95% 6.2 to 2098.5
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0063
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	59.85
	Confidence Interval	(2-Sided) 95% 3.2 to 1128.0
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	347.02
	Confidence Interval	(2-Sided) 95% 18.3 to 6597.9
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)
Description	An ANCOVA model was performed on the log ratio of apoB value at the Pr...
Description	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)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Geometric Mean (95% Confidence Interval) Unit of Measure: percent change
	-3 (-9 to 4)	-15 (-20 to -10)	-8 (-14 to -2)	-9 (-15 to -3)	-16 (-21 to -10)	1 (-5 to 8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4022
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-4
	Confidence Interval	(2-Sided) 95% -12 to 5
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-16
	Confidence Interval	(2-Sided) 95% -23 to -9
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0323
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-9
	Confidence Interval	(2-Sided) 95% -17 to -1
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0157
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-10
	Confidence Interval	(2-Sided) 95% -18 to -2
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-17
	Confidence Interval	(2-Sided) 95% -24 to -9
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

9.Secondary Outcome


Title	Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]
Description	An ANCOVA model was performed on the log ratio of OxPL-apo(a) value at...
Description	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)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Geometric Mean (95% Confidence Interval) Unit of Measure: percent change
	-28 (-41 to -12)	-49 (-58 to -38)	-63 (-70 to -55)	-45 (-55 to -33)	-70 (-75 to -62)	-20 (-35 to -2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4956
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-9
	Confidence Interval	(2-Sided) 95% -32 to 21
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0027
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-36
	Confidence Interval	(2-Sided) 95% -52 to -14
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-54
	Confidence Interval	(2-Sided) 95% -65 to -38
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0114
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-31
	Confidence Interval	(2-Sided) 95% -48 to -8
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-62
	Confidence Interval	(2-Sided) 95% -72 to -49
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

10.Secondary Outcome


Title	Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)
Description	An ANCOVA model was performed on the log ratio of OxPL-apoB value at t...
Description	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)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description:	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description:	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
Overall Number of Participants Analyzed	48	48	47	48	48	47
Geometric Mean (95% Confidence Interval) Unit of Measure: percent change
	-37 (-52 to -17)	-57 (-67 to -45)	-79 (-84 to -73)	-64 (-72 to -53)	-88 (-91 to -84)	14 (-12 to 49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A: ISIS 681257: 20 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0020
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-45
	Confidence Interval	(2-Sided) 95% -62 to -19
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B: ISIS 681257: 40 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-63
	Confidence Interval	(2-Sided) 95% -74 to -46
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort C: ISIS 681257: 60 mg Q4W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-82
	Confidence Interval	(2-Sided) 95% -87 to -73
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort D: ISIS 681257: 20 mg Q2W, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-68
	Confidence Interval	(2-Sided) 95% -78 to -54
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort E: ISIS 681257: 20 mg QW, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference in % CFB
	Estimated Value	-89
	Confidence Interval	(2-Sided) 95% -93 to -84
	Estimation Comments	Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

11.Other Pre-specified Outcome


Title	To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.
Description	Cmax will be calculated for the treatment groups.
Description	Cmax will be calculated for the treatment groups.
Time Frame	6 months

Outcome Measure Data Not Reported

12.Other Pre-specified Outcome


Title	To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.
Description	Tmax will be calculated for the treatment groups.
Description	Tmax will be calculated for the treatment groups.
Time Frame	6 months

Outcome Measure Data Not Reported

13.Other Pre-specified Outcome


Title	To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens.
Description	AUC values will be calculated for the treatment groups.
Description	AUC values will be calculated for the treatment groups.
Time Frame	6 months

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Up to 16 weeks post-treatment period (up to approximately 1.3 years)
Adverse Event Reporting Description	Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo).

Arm/Group Title	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
Arm/Group Description	Cohort A participants received 20 m...	Cohort B participants received 40 m...	Cohort C participants received 60 m...	Cohort D participants received 20 m...	Cohort E participants received 20 m...	Participants in each cohort were ra...
Arm/Group Description	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 participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	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 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.	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.	Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
All-Cause Mortality
	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Serious Adverse Events Serious Adverse Events
	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	7/48 (14.58%)	7/48 (14.58%)	7/47 (14.89%)	3/48 (6.25%)	4/48 (8.33%)	3/47 (6.38%)
Cardiac disorders
Acute myocardial infarction ^† 1	2/48 (4.17%)	0/48 (0.00%)	1/47 (2.13%)	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)
Angina unstable ^† 1	1/48 (2.08%)	0/48 (0.00%)	1/47 (2.13%)	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)
Angina pectoris ^† 1	1/48 (2.08%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)
Coronary artery disease ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Ventricular tachycardia ^† 1	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Gastrointestinal disorders
Oesophagitis haemorrhagic ^† 1	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Pancreatitis acute ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)
General disorders
Malaise ^† 1	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Non-cardiac chest pain ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Cyst ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)
Infections and infestations
Pneumonia ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Upper respiratory tract infection ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Injury, poisoning and procedural complications
Ankle fracture ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Joint dislocation ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Lower limb fracture ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Radius fracture ^† 1	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Road traffic accident ^† 1	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Gastrointestinal anastomotic stenosis ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)
Metabolism and nutrition disorders
Gout ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)
Musculoskeletal and connective tissue disorders
Myalgia ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm ^† 1	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Lung neoplasm malignant ^† 1	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Nervous system disorders
Syncope ^† 1	1/48 (2.08%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Ischaemic stroke ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)
Psychiatric disorders
Acute psychosis ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Depression ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Reproductive system and breast disorders
Vaginal haemorrhage ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
Surgical and medical procedures
Open reduction of fracture ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)
Vascular disorders
Hypertensive crisis ^† 1	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)
1 Term from vocabulary, MedDRA Version 20.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cohort A: ISIS 681257: 20 mg Q4W	Cohort B: ISIS 681257: 40 mg Q4W	Cohort C: ISIS 681257: 60 mg Q4W	Cohort D: ISIS 681257: 20 mg Q2W	Cohort E: ISIS 681257: 20 mg QW	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	38/48 (79.17%)	42/48 (87.50%)	40/47 (85.11%)	36/48 (75.00%)	42/48 (87.50%)	36/47 (76.60%)
Cardiac disorders
Angina pectoris ^† 1	8/48 (16.67%)	3/48 (6.25%)	2/47 (4.26%)	1/48 (2.08%)	2/48 (4.17%)	1/47 (2.13%)
Gastrointestinal disorders
Diarrhoea ^† 1	5/48 (10.42%)	3/48 (6.25%)	2/47 (4.26%)	3/48 (6.25%)	5/48 (10.42%)	3/47 (6.38%)
Nausea ^† 1	3/48 (6.25%)	3/48 (6.25%)	3/47 (6.38%)	0/48 (0.00%)	2/48 (4.17%)	1/47 (2.13%)
Vomiting ^† 1	1/48 (2.08%)	3/48 (6.25%)	2/47 (4.26%)	3/48 (6.25%)	1/48 (2.08%)	0/47 (0.00%)
General disorders
Injection site erythema ^† 1	3/48 (6.25%)	13/48 (27.08%)	13/47 (27.66%)	11/48 (22.92%)	22/48 (45.83%)	0/47 (0.00%)
Fatigue ^† 1	8/48 (16.67%)	7/48 (14.58%)	2/47 (4.26%)	1/48 (2.08%)	3/48 (6.25%)	1/47 (2.13%)
Injection site pain ^† 1	2/48 (4.17%)	2/48 (4.17%)	3/47 (6.38%)	1/48 (2.08%)	3/48 (6.25%)	0/47 (0.00%)
Influenza like illness ^† 1	3/48 (6.25%)	2/48 (4.17%)	4/47 (8.51%)	1/48 (2.08%)	0/48 (0.00%)	2/47 (4.26%)
Injection site pruritus ^† 1	1/48 (2.08%)	4/48 (8.33%)	1/47 (2.13%)	2/48 (4.17%)	2/48 (4.17%)	0/47 (0.00%)
Oedema peripheral ^† 1	1/48 (2.08%)	2/48 (4.17%)	2/47 (4.26%)	2/48 (4.17%)	0/48 (0.00%)	4/47 (8.51%)
Pyrexia ^† 1	0/48 (0.00%)	3/48 (6.25%)	1/47 (2.13%)	0/48 (0.00%)	2/48 (4.17%)	3/47 (6.38%)
Injection site bruising ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	0/48 (0.00%)	4/48 (8.33%)	0/47 (0.00%)
Immune system disorders
Seasonal allergy ^† 1	0/48 (0.00%)	1/48 (2.08%)	2/47 (4.26%)	1/48 (2.08%)	2/48 (4.17%)	3/47 (6.38%)
Infections and infestations
Viral upper respiratory tract infection ^† 1	8/48 (16.67%)	10/48 (20.83%)	8/47 (17.02%)	8/48 (16.67%)	15/48 (31.25%)	11/47 (23.40%)
Urinary tract infection ^† 1	7/48 (14.58%)	7/48 (14.58%)	10/47 (21.28%)	6/48 (12.50%)	9/48 (18.75%)	3/47 (6.38%)
Sinusitis ^† 1	2/48 (4.17%)	2/48 (4.17%)	4/47 (8.51%)	4/48 (8.33%)	3/48 (6.25%)	3/47 (6.38%)
Upper respiratory tract infection ^† 1	4/48 (8.33%)	3/48 (6.25%)	0/47 (0.00%)	3/48 (6.25%)	4/48 (8.33%)	5/47 (10.64%)
Influenza ^† 1	5/48 (10.42%)	0/48 (0.00%)	2/47 (4.26%)	2/48 (4.17%)	5/48 (10.42%)	1/47 (2.13%)
Gastroenteritis ^† 1	2/48 (4.17%)	1/48 (2.08%)	1/47 (2.13%)	2/48 (4.17%)	4/48 (8.33%)	3/47 (6.38%)
Bronchitis ^† 1	1/48 (2.08%)	0/48 (0.00%)	2/47 (4.26%)	2/48 (4.17%)	0/48 (0.00%)	3/47 (6.38%)
Conjunctivitis ^† 1	0/48 (0.00%)	0/48 (0.00%)	0/47 (0.00%)	3/48 (6.25%)	1/48 (2.08%)	0/47 (0.00%)
Injury, poisoning and procedural complications
Contusion ^† 1	2/48 (4.17%)	0/48 (0.00%)	1/47 (2.13%)	3/48 (6.25%)	3/48 (6.25%)	0/47 (0.00%)
Fall ^† 1	2/48 (4.17%)	3/48 (6.25%)	0/47 (0.00%)	1/48 (2.08%)	2/48 (4.17%)	0/47 (0.00%)
Investigations
Blood creatine phosphokinase increased ^† 1	5/48 (10.42%)	1/48 (2.08%)	1/47 (2.13%)	3/48 (6.25%)	3/48 (6.25%)	2/47 (4.26%)
Blood bilirubin increased ^† 1	1/48 (2.08%)	0/48 (0.00%)	2/47 (4.26%)	2/48 (4.17%)	5/48 (10.42%)	3/47 (6.38%)
Laboratory test abnormal ^† 1	3/48 (6.25%)	1/48 (2.08%)	1/47 (2.13%)	3/48 (6.25%)	1/48 (2.08%)	1/47 (2.13%)
Alanine aminotransferase increased ^† 1	2/48 (4.17%)	1/48 (2.08%)	0/47 (0.00%)	1/48 (2.08%)	3/48 (6.25%)	0/47 (0.00%)
Musculoskeletal and connective tissue disorders
Myalgia ^† 1	4/48 (8.33%)	5/48 (10.42%)	10/47 (21.28%)	6/48 (12.50%)	3/48 (6.25%)	5/47 (10.64%)
Arthralgia ^† 1	1/48 (2.08%)	5/48 (10.42%)	4/47 (8.51%)	2/48 (4.17%)	4/48 (8.33%)	2/47 (4.26%)
Back pain ^† 1	2/48 (4.17%)	7/48 (14.58%)	2/47 (4.26%)	1/48 (2.08%)	4/48 (8.33%)	3/47 (6.38%)
Pain in extremity ^† 1	4/48 (8.33%)	2/48 (4.17%)	3/47 (6.38%)	1/48 (2.08%)	3/48 (6.25%)	1/47 (2.13%)
Neck pain ^† 1	1/48 (2.08%)	1/48 (2.08%)	4/47 (8.51%)	3/48 (6.25%)	1/48 (2.08%)	1/47 (2.13%)
Muscle spasms ^† 1	3/48 (6.25%)	1/48 (2.08%)	0/47 (0.00%)	2/48 (4.17%)	3/48 (6.25%)	2/47 (4.26%)
Musculoskeletal pain ^† 1	1/48 (2.08%)	3/48 (6.25%)	0/47 (0.00%)	1/48 (2.08%)	1/48 (2.08%)	2/47 (4.26%)
Musculoskeletal stiffness ^† 1	0/48 (0.00%)	0/48 (0.00%)	1/47 (2.13%)	0/48 (0.00%)	3/48 (6.25%)	0/47 (0.00%)
Flank pain ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	0/48 (0.00%)	3/47 (6.38%)
Nervous system disorders
Headache ^† 1	6/48 (12.50%)	7/48 (14.58%)	4/47 (8.51%)	4/48 (8.33%)	6/48 (12.50%)	5/47 (10.64%)
Dizziness ^† 1	4/48 (8.33%)	3/48 (6.25%)	4/47 (8.51%)	2/48 (4.17%)	4/48 (8.33%)	2/47 (4.26%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	2/48 (4.17%)	3/48 (6.25%)	3/47 (6.38%)	2/48 (4.17%)	6/48 (12.50%)	5/47 (10.64%)
Oropharyngeal pain ^† 1	3/48 (6.25%)	3/48 (6.25%)	4/47 (8.51%)	1/48 (2.08%)	5/48 (10.42%)	1/47 (2.13%)
Dyspnoea ^† 1	2/48 (4.17%)	5/48 (10.42%)	0/47 (0.00%)	1/48 (2.08%)	3/48 (6.25%)	2/47 (4.26%)
Rhinorrhoea ^† 1	3/48 (6.25%)	0/48 (0.00%)	1/47 (2.13%)	1/48 (2.08%)	2/48 (4.17%)	1/47 (2.13%)
Nasal congestion ^† 1	1/48 (2.08%)	3/48 (6.25%)	0/47 (0.00%)	0/48 (0.00%)	1/48 (2.08%)	2/47 (4.26%)
Epistaxis ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	2/48 (4.17%)	1/48 (2.08%)	4/47 (8.51%)
Skin and subcutaneous tissue disorders
Dermatitis ^† 1	0/48 (0.00%)	1/48 (2.08%)	0/47 (0.00%)	0/48 (0.00%)	3/48 (6.25%)	1/47 (2.13%)
Vascular disorders
Hypertension ^† 1	3/48 (6.25%)	1/48 (2.08%)	3/47 (6.38%)	4/48 (8.33%)	4/48 (8.33%)	2/47 (4.26%)
1 Term from vocabulary, MedDRA Version 20.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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Name/Title:	Study Director
Organization:	Akcea Therapeutics
Phone:	617-207-0289
EMail:	clinicalstudies@akceatx.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

Layout table for additonal information

Responsible Party:	Akcea Therapeutics
ClinicalTrials.gov Identifier:	NCT03070782
Other Study ID Numbers:	ISIS 681257-CS6 2016-003373-18 ( EudraCT Number )
First Submitted:	January 31, 2017
First Posted:	March 6, 2017
Results First Submitted:	September 30, 2020
Results First Posted:	October 30, 2020
Last Update Posted:	October 30, 2020

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