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Clinical Trial Results:
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

Summary
EudraCT number	2016-003373-18
Trial protocol	DE NL DK
Global end of trial date	13 Nov 2018

Results information
Results version number	v1(current)
This version publication date	16 Oct 2020
First version publication date	16 Oct 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ISIS681257-CS6

ISRCTN number

US NCT number

NCT03070782

WHO universal trial number (UTN)

Sponsor organisation name

Akcea Therapeutics

Sponsor organisation address

22 Boston Wharf Rd, 9th Floor, Boston, Massachusetts, United States, 02210

Public contact

Study Director, Akcea Therapeutics- An Affiliate of Ionis Pharmaceuticals, Inc., +1 6172070289, clinicalstudies@akceatx.com

Scientific contact

Study Director, Akcea Therapeutics- An Affiliate of Ionis Pharmaceuticals, Inc., +1 6172070289, clinicalstudies@akceatx.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Nov 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Nov 2018

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study is 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 CVD.

Protection of trial subjects

This study was conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines to ensure the safety of participants. Before commencement of the trial, the Investigator was responsible for obtaining written informed consent from the participant or legally acceptable representative after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures or any study drug (ISIS 681257 or placebo) were administered. The protocol provided prespecified safety monitoring rules. An independent Data and Safety Monitoring (DSMB) was also assembled to review safety, tolerability and efficacy (as needed) data collected during the study and provided recommendations to the sponsor for modifying, stopping or continuing the study as planned.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Mar 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

4 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 16

Country: Number of subjects enrolled

Denmark: 25

Country: Number of subjects enrolled

Germany: 48

Country: Number of subjects enrolled

Canada: 57

Country: Number of subjects enrolled

United States: 140

Worldwide total number of subjects

286

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

178

From 65 to 84 years

108

85 years and over

Subject disposition

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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.

Screening 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. 250 participants completed the treatment period. 263 of 286 participants completed the follow-up period. Here, Completed refers to participants who completed study treatment

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Cohort A: ISIS 681257: 20 mg Q4W

Arm 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.

Arm type

Experimental

Investigational medicinal product name

ISIS 681257

Investigational medicinal product code

ISIS 681257

Other name

AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Pharmaceutical forms

Injection, Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

ISIS 681257 at dose 20 milligrams (mg), administered via subcutaneous (SC) injection, once every 4 weeks (Q4W).

Cohort B: ISIS 681257: 40 mg Q4W

Arm description

Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Arm type

Experimental

Investigational medicinal product name

ISIS 681257

Investigational medicinal product code

ISIS 681257

Other name

AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Pharmaceutical forms

Solution for injection, Injection

Routes of administration

Subcutaneous use

Dosage and administration details

ISIS 681257 at dose 20 milligrams (mg), administered via subcutaneous (SC) injection, once every 4 weeks (Q4W).

Cohort C: ISIS 681257: 60 mg Q4W

Arm description

Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Arm type

Experimental

Investigational medicinal product name

ISIS 681257

Investigational medicinal product code

ISIS 681257

Other name

AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Pharmaceutical forms

Solution for injection, Injection

Routes of administration

Subcutaneous use

Dosage and administration details

ISIS 681257 at dose 20 milligrams (mg), administered via subcutaneous (SC) injection, once every 4 weeks (Q4W).

Cohort D: ISIS 681257: 20 mg Q2W

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

ISIS 681257

Investigational medicinal product code

ISIS 681257

Other name

AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Pharmaceutical forms

Injection, Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

ISIS 681257 at dose 20 milligrams (mg), administered via subcutaneous (SC) injection, once every 4 weeks (Q4W).

Cohort E: ISIS 681257: 20 mg QW

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

ISIS 681257

Investigational medicinal product code

ISIS 681257

Other name

AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Pharmaceutical forms

Injection, Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

ISIS 681257 at dose 20 milligrams (mg), administered via subcutaneous (SC) injection, once every 4 weeks (Q4W).

Placebo

Arm description

Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection, Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sterile normal saline (0.9% NaCl)

Number of subjects in period 1	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
Started	48	48	47	48	48	47
Completed	41	47	43	43	36	40
Not completed	7	1	4	5	12	7
Adverse event, serious fatal	3	-	3	1	6	2
Consent withdrawn by subject	2	1	1	-	4	3
Investigator judgement	-	-	-	1	-	-
Pregnancy	-	-	-	1	-	-
Reason not specified	2	-	-	1	2	1
Ineligibility	-	-	-	1	-	1

Baseline characteristics

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Reporting group title

Cohort A: ISIS 681257: 20 mg Q4W

Reporting 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.

Reporting group title

Cohort B: ISIS 681257: 40 mg Q4W

Reporting group description

Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Reporting group title

Cohort C: ISIS 681257: 60 mg Q4W

Reporting group description

Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Reporting group title

Cohort D: ISIS 681257: 20 mg Q2W

Reporting group description

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.

Reporting group title

Cohort E: ISIS 681257: 20 mg QW

Reporting group description

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.

Reporting group title

Placebo

Reporting group description

Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).

Reporting group values	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
Number of subjects	48	48	47	48	48	47	286
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	32	28	25	30	35	28	178
From 65-84 years	16	20	22	18	13	19	108
85 years and over	0	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	60.0 ( 9.62 )	61.3 ( 10.55 )	62.2 ( 9.69 )	57.9 ( 11.48 )	58.9 ( 7.98 )	59.9 ( 10.49 )	-
Gender categorical
Units: Subjects
Female	19	12	14	17	20	15	97
Male	29	36	33	31	28	32	189
Race
Units: Subjects
White	44	45	47	47	47	46	276
Black or African American	2	3	0	0	1	0	6
Asian	1	0	0	0	0	1	2
American Indian or Alaskan Native	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Unknown or Not Reported	1	0	0	1	0	0	2
Ethnicity
Units: Subjects
Hispanic or Latino	2	1	0	0	1	1	5
Not Hispanic or Latino	46	47	47	48	47	46	281

End points

Top of page

Reporting group title

Cohort A: ISIS 681257: 20 mg Q4W

Reporting 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.

Reporting group title

Cohort B: ISIS 681257: 40 mg Q4W

Reporting group description

Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Reporting group title

Cohort C: ISIS 681257: 60 mg Q4W

Reporting group description

Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Reporting group title

Cohort D: ISIS 681257: 20 mg Q2W

Reporting group description

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.

Reporting group title

Cohort E: ISIS 681257: 20 mg QW

Reporting group description

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.

Reporting group title

Placebo

Reporting group description

Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).

Primary: Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

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End point title

Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

End point 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. 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.

End point type

Primary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percent change
geometric mean (confidence interval 95%)	-35 (-45 to -22)	-56 (-63 to -48)	-72 (-76 to -67)	-58 (-65 to -50)	-80 (-83 to -76)	-6 (-21 to 12)

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Cohort A: ISIS 681257: 20 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0032

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-31

Confidence interval

level

95%

sides

2-sided

lower limit

-46

upper limit

-12

Notes
[1] - 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.

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Placebo v Cohort B: ISIS 681257: 40 mg Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-54

Confidence interval

level

95%

sides

2-sided

lower limit

-64

upper limit

-41

Notes
[2] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-70

Confidence interval

level

95%

sides

2-sided

lower limit

-77

upper limit

-62

Notes
[3] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-56

Confidence interval

level

95%

sides

2-sided

lower limit

-65

upper limit

-43

Notes
[4] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-78

Confidence interval

level

95%

sides

2-sided

lower limit

-83

upper limit

-72

Notes
[5] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

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End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs) ^[6]

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

End point type

Primary

End point timeframe

Up to 16 weeks post treatment period (up to approximately 1.3 years)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses was performed for this end point.

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: participants	46	43	43	41	44	41

No statistical analyses for this end point

Primary: Number of Participants With TEAEs by Maximum Severity

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End point title

Number of Participants With TEAEs by Maximum Severity ^[7]

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

End point type

Primary

End point timeframe

Up to 16 weeks post treatment period (up to approximately 1.3 years)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses was performed for this end point.

End point values	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
Number of subjects analysed	46 ^[8]	43 ^[9]	43 ^[10]	41 ^[11]	44 ^[12]	41 ^[13]
Units: participants
Mild	20	21	16	24	21	22
Moderate	20	19	21	15	20	16
Severe	6	3	6	2	3	3

Notes
[8] - Only participants with at least one TEAE were analyzed for this outcome measure.
[9] - Only participants with at least one TEAE were analyzed for this outcome measure.
[10] - Only participants with at least one TEAE were analyzed for this outcome measure.
[11] - Only participants with at least one TEAE were analyzed for this outcome measure.
[12] - Only participants with at least one TEAE were analyzed for this outcome measure.
[13] - Only participants with at least one TEAE were analyzed for this outcome measure.

No statistical analyses for this end point

Primary: Number of Participants With TEAEs Leading to Study Discontinuation

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End point title

Number of Participants With TEAEs Leading to Study Discontinuation ^[14]

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

End point type

Primary

End point timeframe

Up to 16 weeks post treatment period (up to approximately 1.3 years)

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses was performed for this end point.

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: participants	3	0	3	1	6	2

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

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End point title

Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

End point 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. 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.

End point type

Secondary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percent change
geometric mean (confidence interval 95%)	-7 (-16 to 3)	-26 (-33 to -18)	-16 (-24 to -7)	-17 (-25 to -8)	-23 (-31 to -14)	-1 (-11 to 9)

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Cohort A: ISIS 681257: 20 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.4407

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-19

upper limit

Notes
[15] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Cohort B: ISIS 681257: 40 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-25

Confidence interval

level

95%

sides

2-sided

lower limit

-35

upper limit

-13

Notes
[16] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.0368

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-14

Confidence interval

level

95%

sides

2-sided

lower limit

-26

upper limit

-1

Notes
[17] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.0216

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-16

Confidence interval

level

95%

sides

2-sided

lower limit

-28

upper limit

-3

Notes
[18] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0012

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-22

Confidence interval

level

95%

sides

2-sided

lower limit

-33

upper limit

-9

Notes
[19] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

Top of page

End point title

Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

End point 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. 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.

End point type

Secondary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percentage of participants
number (not applicable)	22.9	62.5	80.9	64.6	97.9	6.4

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Cohort A: ISIS 681257: 20 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0286

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

4.98

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Cohort B: ISIS 681257: 40 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

31.07

Confidence interval

level

95%

sides

2-sided

lower limit

7.3

upper limit

131.4

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

122.81

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

627.4

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

43.78

Confidence interval

level

95%

sides

2-sided

lower limit

9.8

upper limit

195

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1124.56

Confidence interval

level

95%

sides

2-sided

lower limit

109.3

upper limit

11571

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 nmol/L or ≤ 30 mg/dL

Top of page

End point title

Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 nmol/L or ≤ 30 mg/dL

End point 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. 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.

End point type

Secondary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percentage of participants
number (not applicable)	6.3	25.0	53.2	33.3	70.8	0

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Cohort A: ISIS 681257: 20 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2007

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

7.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

155.3

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Cohort B: ISIS 681257: 40 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0258

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

27.92

Confidence interval

level

95%

sides

2-sided

lower limit

1.5

upper limit

521.5

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0014

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

113.92

Confidence interval

level

95%

sides

2-sided

lower limit

6.2

upper limit

2098.5

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0063

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

59.85

Confidence interval

level

95%

sides

2-sided

lower limit

3.2

upper limit

1128

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

347.02

Confidence interval

level

95%

sides

2-sided

lower limit

18.3

upper limit

6597.9

Secondary: Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

Top of page

End point title

Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

End point 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. 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.

End point type

Secondary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percent change
geometric mean (confidence interval 95%)	-3 (-9 to 4)	-15 (-20 to -10)	-8 (-14 to -2)	-9 (-15 to -3)	-16 (-21 to -10)	1 (-5 to 8)

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Placebo v Cohort A: ISIS 681257: 20 mg Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.4022

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

Notes
[20] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Cohort B: ISIS 681257: 40 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-16

Confidence interval

level

95%

sides

2-sided

lower limit

-23

upper limit

-9

Notes
[21] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.0323

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-17

upper limit

-1

Notes
[22] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.0157

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-10

Confidence interval

level

95%

sides

2-sided

lower limit

-18

upper limit

-2

Notes
[23] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-17

Confidence interval

level

95%

sides

2-sided

lower limit

-24

upper limit

-9

Notes
[24] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

Top of page

End point title

Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

End point 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 percent change in OxPL-apo(a) value at the Primary Analysis Time Point tocorresponding time/percent change in 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.

End point type

Secondary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percent change
geometric mean (confidence interval 95%)	-28 (-41 to -12)	-49 (-58 to -38)	-63 (-70 to -55)	-45 (-55 to -33)	-70 (-75 to -62)	-20 (-35 to -2)

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Cohort A: ISIS 681257: 20 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.4956

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-32

upper limit

Notes
[25] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Cohort B: ISIS 681257: 40 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.0027

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-36

Confidence interval

level

95%

sides

2-sided

lower limit

-52

upper limit

-14

Notes
[26] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-54

Confidence interval

level

95%

sides

2-sided

lower limit

-65

upper limit

-38

Notes
[27] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.0114

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-31

Confidence interval

level

95%

sides

2-sided

lower limit

-48

upper limit

-8

Notes
[28] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-62

Confidence interval

level

95%

sides

2-sided

lower limit

-72

upper limit

-49

Notes
[29] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

Top of page

End point title

Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

End point 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. 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.

End point type

Secondary

End point timeframe

Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

End point values	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
Number of subjects analysed	48	48	47	48	48	47
Units: percent change
geometric mean (confidence interval 95%)	-37 (-52 to -17)	-57 (-67 to -45)	-79 (-84 to -73)	-64 (-72 to -53)	-88 (-91 to -84)	14 (-12 to 49)

Cohort A: ISIS 681257: 20 mg Q4W versus Placebo

Comparison groups

Cohort A: ISIS 681257: 20 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.002

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-45

Confidence interval

level

95%

sides

2-sided

lower limit

-62

upper limit

-19

Notes
[30] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort B: ISIS 681257: 40 mg Q4W versus Placebo

Comparison groups

Cohort B: ISIS 681257: 40 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-63

Confidence interval

level

95%

sides

2-sided

lower limit

-74

upper limit

-46

Notes
[31] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort C: ISIS 681257: 60 mg Q4W versus Placebo

Comparison groups

Cohort C: ISIS 681257: 60 mg Q4W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-82

Confidence interval

level

95%

sides

2-sided

lower limit

-87

upper limit

-73

Notes
[32] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort D: ISIS 681257: 20 mg Q2W versus Placebo

Comparison groups

Cohort D: ISIS 681257: 20 mg Q2W v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-68

Confidence interval

level

95%

sides

2-sided

lower limit

-78

upper limit

-54

Notes
[33] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Cohort E: ISIS 681257: 20 mg QW versus Placebo

Comparison groups

Cohort E: ISIS 681257: 20 mg QW v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean Difference in % CFB

Point estimate

-89

Confidence interval

level

95%

sides

2-sided

lower limit

-93

upper limit

-84

Notes
[34] - Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated.

Adverse events

Top of page

Timeframe for reporting adverse events

Up to 16 weeks post-treatment period (up to approximately 1.3 years )

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Cohort A: ISIS 681257: 20mg Q4W

Reporting 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.

Reporting group title

Cohort B: ISIS 681257: 40mg Q4W

Reporting group description

Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Reporting group title

Cohort C: ISIS 681257: 60mg Q4W

Reporting group description

Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.

Reporting group title

Cohort D: ISIS 681257: 20mg Q2W

Reporting group description

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.

Reporting group title

Cohort E: ISIS 681257: 20mg QW

Reporting group description

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.

Reporting group title

Placebo

Reporting group description

Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).

Serious adverse events	Cohort A: ISIS 681257: 20mg Q4W	Cohort B: ISIS 681257: 40mg Q4W	Cohort C: ISIS 681257: 60mg Q4W	Cohort D: ISIS 681257: 20mg Q2W	Cohort E: ISIS 681257: 20mg QW	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 48 (14.58%)	7 / 48 (14.58%)	7 / 47 (14.89%)	3 / 48 (6.25%)	4 / 48 (8.33%)	3 / 47 (6.38%)
number of deaths (all causes)	0	0	1	0	1	0
number of deaths resulting from adverse events	0	0	1	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Open reduction of fracture
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Malaise
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cyst
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Acute psychosis
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Gastrointestinal anastomotic stenosis
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	2 / 48 (4.17%)	0 / 48 (0.00%)	1 / 47 (2.13%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 47 (2.13%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 48 (2.08%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Oesophagitis haemorrhagic
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort A: ISIS 681257: 20mg Q4W	Cohort B: ISIS 681257: 40mg Q4W	Cohort C: ISIS 681257: 60mg Q4W	Cohort D: ISIS 681257: 20mg Q2W	Cohort E: ISIS 681257: 20mg QW	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 48 (79.17%)	42 / 48 (87.50%)	40 / 47 (85.11%)	36 / 48 (75.00%)	42 / 48 (87.50%)	36 / 47 (76.60%)
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	5 / 48 (10.42%)	1 / 48 (2.08%)	1 / 47 (2.13%)	3 / 48 (6.25%)	3 / 48 (6.25%)	2 / 47 (4.26%)
occurrences all number	7	2	2	4	3	2
Blood bilirubin increased
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	2 / 47 (4.26%)	2 / 48 (4.17%)	5 / 48 (10.42%)	3 / 47 (6.38%)
occurrences all number	2	0	2	3	6	5
Laboratory test abnormal
subjects affected / exposed	3 / 48 (6.25%)	1 / 48 (2.08%)	1 / 47 (2.13%)	3 / 48 (6.25%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences all number	4	1	1	3	1	1
Alanine aminotransferase increased
subjects affected / exposed	2 / 48 (4.17%)	1 / 48 (2.08%)	0 / 47 (0.00%)	1 / 48 (2.08%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	4	1	0	1	3	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 48 (4.17%)	0 / 48 (0.00%)	1 / 47 (2.13%)	3 / 48 (6.25%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	4	0	1	3	3	0
Fall
subjects affected / exposed	2 / 48 (4.17%)	3 / 48 (6.25%)	0 / 47 (0.00%)	1 / 48 (2.08%)	2 / 48 (4.17%)	0 / 47 (0.00%)
occurrences all number	2	4	0	1	2	0
Vascular disorders
Hypertension
subjects affected / exposed	3 / 48 (6.25%)	1 / 48 (2.08%)	3 / 47 (6.38%)	4 / 48 (8.33%)	4 / 48 (8.33%)	2 / 47 (4.26%)
occurrences all number	3	1	4	4	4	2
Cardiac disorders
Angina pectoris
subjects affected / exposed	8 / 48 (16.67%)	3 / 48 (6.25%)	2 / 47 (4.26%)	1 / 48 (2.08%)	2 / 48 (4.17%)	1 / 47 (2.13%)
occurrences all number	8	5	10	1	2	1
Nervous system disorders
Headache
subjects affected / exposed	6 / 48 (12.50%)	7 / 48 (14.58%)	4 / 47 (8.51%)	4 / 48 (8.33%)	6 / 48 (12.50%)	5 / 47 (10.64%)
occurrences all number	9	11	8	7	8	5
Dizziness
subjects affected / exposed	4 / 48 (8.33%)	3 / 48 (6.25%)	4 / 47 (8.51%)	2 / 48 (4.17%)	4 / 48 (8.33%)	2 / 47 (4.26%)
occurrences all number	5	3	4	3	4	4
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	3 / 48 (6.25%)	13 / 48 (27.08%)	13 / 47 (27.66%)	11 / 48 (22.92%)	22 / 48 (45.83%)	0 / 47 (0.00%)
occurrences all number	4	31	31	58	113	0
Fatigue
subjects affected / exposed	8 / 48 (16.67%)	7 / 48 (14.58%)	2 / 47 (4.26%)	1 / 48 (2.08%)	3 / 48 (6.25%)	1 / 47 (2.13%)
occurrences all number	8	9	2	1	3	1
Injection site pain
subjects affected / exposed	2 / 48 (4.17%)	2 / 48 (4.17%)	3 / 47 (6.38%)	1 / 48 (2.08%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	2	2	3	1	4	0
Influenza like illness
subjects affected / exposed	3 / 48 (6.25%)	2 / 48 (4.17%)	4 / 47 (8.51%)	1 / 48 (2.08%)	0 / 48 (0.00%)	2 / 47 (4.26%)
occurrences all number	3	2	4	1	0	2
Injection site pruritus
subjects affected / exposed	1 / 48 (2.08%)	4 / 48 (8.33%)	1 / 47 (2.13%)	2 / 48 (4.17%)	2 / 48 (4.17%)	0 / 47 (0.00%)
occurrences all number	1	8	1	2	3	0
Oedema peripheral
subjects affected / exposed	1 / 48 (2.08%)	2 / 48 (4.17%)	2 / 47 (4.26%)	2 / 48 (4.17%)	0 / 48 (0.00%)	4 / 47 (8.51%)
occurrences all number	1	3	2	3	0	5
Pyrexia
subjects affected / exposed	0 / 48 (0.00%)	3 / 48 (6.25%)	1 / 47 (2.13%)	0 / 48 (0.00%)	2 / 48 (4.17%)	3 / 47 (6.38%)
occurrences all number	0	7	1	0	2	3
Injection site bruising
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	4 / 48 (8.33%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	6	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	2 / 47 (4.26%)	1 / 48 (2.08%)	2 / 48 (4.17%)	3 / 47 (6.38%)
occurrences all number	0	1	3	1	2	3
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	5 / 48 (10.42%)	3 / 48 (6.25%)	2 / 47 (4.26%)	3 / 48 (6.25%)	5 / 48 (10.42%)	1 / 47 (2.13%)
occurrences all number	7	3	2	4	7	4
Nausea
subjects affected / exposed	3 / 48 (6.25%)	3 / 48 (6.25%)	3 / 47 (6.38%)	0 / 48 (0.00%)	2 / 48 (4.17%)	1 / 47 (2.13%)
occurrences all number	3	3	3	0	2	1
Vomiting
subjects affected / exposed	1 / 48 (2.08%)	3 / 48 (6.25%)	2 / 47 (4.26%)	3 / 48 (6.25%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences all number	1	3	2	3	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 48 (4.17%)	3 / 48 (6.25%)	3 / 47 (6.38%)	2 / 48 (4.17%)	6 / 48 (12.50%)	5 / 47 (10.64%)
occurrences all number	3	3	3	2	9	5
Oropharyngeal pain
subjects affected / exposed	3 / 48 (6.25%)	3 / 48 (6.25%)	4 / 47 (8.51%)	1 / 48 (2.08%)	5 / 48 (10.42%)	1 / 47 (2.13%)
occurrences all number	3	3	4	2	6	1
Dyspnoea
subjects affected / exposed	2 / 48 (4.17%)	5 / 48 (10.42%)	0 / 47 (0.00%)	1 / 48 (2.08%)	3 / 48 (6.25%)	2 / 47 (4.26%)
occurrences all number	2	5	0	1	3	2
Rhinorrhoea
subjects affected / exposed	3 / 48 (6.25%)	0 / 48 (0.00%)	1 / 47 (2.13%)	1 / 48 (2.08%)	2 / 48 (4.17%)	1 / 47 (2.13%)
occurrences all number	3	0	1	1	2	1
Nasal congestion
subjects affected / exposed	1 / 48 (2.08%)	3 / 48 (6.25%)	0 / 47 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	2 / 47 (4.26%)
occurrences all number	2	3	0	0	3	2
Epistaxis
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	2 / 48 (4.17%)	1 / 48 (2.08%)	4 / 47 (8.51%)
occurrences all number	0	1	0	2	1	7
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	3 / 48 (6.25%)	1 / 47 (2.13%)
occurrences all number	0	1	0	0	3	1
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	4 / 48 (8.33%)	5 / 48 (10.42%)	10 / 47 (21.28%)	6 / 48 (12.50%)	3 / 48 (6.25%)	5 / 47 (10.64%)
occurrences all number	5	6	16	23	4	6
Arthralgia
subjects affected / exposed	1 / 48 (2.08%)	5 / 48 (10.42%)	4 / 47 (8.51%)	2 / 48 (4.17%)	4 / 48 (8.33%)	2 / 47 (4.26%)
occurrences all number	1	6	6	2	5	3
Back pain
subjects affected / exposed	2 / 48 (4.17%)	7 / 48 (14.58%)	2 / 47 (4.26%)	1 / 48 (2.08%)	4 / 48 (8.33%)	3 / 47 (6.38%)
occurrences all number	2	9	2	1	4	3
Pain in extremity
subjects affected / exposed	4 / 48 (8.33%)	2 / 48 (4.17%)	3 / 47 (6.38%)	1 / 48 (2.08%)	3 / 48 (6.25%)	1 / 47 (2.13%)
occurrences all number	5	2	4	1	4	1
Neck pain
subjects affected / exposed	1 / 48 (2.08%)	1 / 48 (2.08%)	4 / 47 (8.51%)	3 / 48 (6.25%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences all number	1	1	4	3	1	1
Muscle spasms
subjects affected / exposed	3 / 48 (6.25%)	1 / 48 (2.08%)	0 / 47 (0.00%)	2 / 48 (4.17%)	3 / 48 (6.25%)	2 / 47 (4.26%)
occurrences all number	4	1	0	2	3	2
Musculoskeletal pain
subjects affected / exposed	1 / 48 (2.08%)	3 / 48 (6.25%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	2 / 47 (4.26%)
occurrences all number	1	3	0	1	1	2
Musculoskeletal stiffness
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	3	0
Flank pain
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	1	0	0	0	3
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	8 / 48 (16.67%)	10 / 48 (20.83%)	8 / 47 (17.02%)	8 / 48 (16.67%)	15 / 48 (31.25%)	11 / 47 (23.40%)
occurrences all number	8	12	10	11	21	17
Urinary tract infection
subjects affected / exposed	7 / 48 (14.58%)	7 / 48 (14.58%)	10 / 47 (21.28%)	6 / 48 (12.50%)	9 / 48 (18.75%)	3 / 47 (6.38%)
occurrences all number	10	12	18	6	13	4
Sinusitis
subjects affected / exposed	2 / 48 (4.17%)	2 / 48 (4.17%)	4 / 47 (8.51%)	4 / 48 (8.33%)	3 / 48 (6.25%)	3 / 47 (6.38%)
occurrences all number	2	2	4	4	4	3
Upper respiratory tract infection
subjects affected / exposed	4 / 48 (8.33%)	3 / 48 (6.25%)	0 / 47 (0.00%)	3 / 48 (6.25%)	4 / 48 (8.33%)	5 / 47 (10.64%)
occurrences all number	5	3	0	3	5	5
Influenza
subjects affected / exposed	5 / 48 (10.42%)	0 / 48 (0.00%)	2 / 47 (4.26%)	2 / 48 (4.17%)	5 / 48 (10.42%)	1 / 47 (2.13%)
occurrences all number	6	0	2	2	7	1
Gastroenteritis
subjects affected / exposed	2 / 48 (4.17%)	1 / 48 (2.08%)	1 / 47 (2.13%)	2 / 48 (4.17%)	4 / 48 (8.33%)	3 / 47 (6.38%)
occurrences all number	2	1	1	2	4	3
Bronchitis
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	2 / 47 (4.26%)	2 / 48 (4.17%)	0 / 48 (0.00%)	3 / 47 (6.38%)
occurrences all number	1	0	2	2	0	3
Conjunctivitis
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)	3 / 48 (6.25%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences all number	0	0	0	3	2	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Oct 2016

Regulatory advice on inclusion of more detailed description of processes for platelet monitoring, and more frequent monitoring of liver function.

29 Nov 2016

Regulatory advice on inclusion of biomarkers of renal damage and increased frequency of renal monitoring. Addition of a Data Safety Monitoring Board.

30 Dec 2016

Adjustment of the frequency, and alert and intervention limits, for renal safety and adjustment of the frequency of liver safety testing.

05 Jan 2017

The study population was increased to 270 participants (54 per cohort) to support a statistical assessment of risk of platelet reduction in this population. In addition, the 10 mg weekly treatment cohort was modified to 20 mg every 2 weeks (biweekly).

30 May 2017

Regulatory advice on addition of exclusion criteria, reduced permitted timeframe for identifying critical laboratory results by the investigator and replacement of the Adverse Event (AE) definition.

25 Jan 2018

Updated platelet monitoring to allow for potential to return to every 2-week monitoring, clarified definition and scheduling of the follow-up period and End of Treatment visit for last participant to complete primary endpoint visit.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

Primary: Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Primary: Number of Participants With TEAEs by Maximum Severity

Primary: Number of Participants With TEAEs by Maximum Severity

Primary: Number of Participants With TEAEs Leading to Study Discontinuation

Primary: Number of Participants With TEAEs Leading to Study Discontinuation

Secondary: Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

Secondary: Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 nmol/L or ≤ 30 mg/dL

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 nmol/L or ≤ 30 mg/dL

Secondary: Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

Secondary: Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

Primary: Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Primary: Number of Participants With TEAEs by Maximum Severity

Primary: Number of Participants With TEAEs by Maximum Severity

Primary: Number of Participants With TEAEs Leading to Study Discontinuation

Primary: Number of Participants With TEAEs Leading to Study Discontinuation

Secondary: Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

Secondary: Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 nmol/L or ≤ 30 mg/dL

Secondary: Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 nmol/L or ≤ 30 mg/dL

Secondary: Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

Secondary: Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

Secondary: Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)