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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
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
Hide 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.
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
Hide 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
Hide 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%
1.Primary Outcome
Title Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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)]
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide 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.
Hide Description AUC values will be calculated for the treatment groups.
Time Frame 6 months
Outcome Measure Data Not Reported
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
Hide 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%) 
Hide 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
Hide 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
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
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Akcea Therapeutics
Phone: 617-207-0289
EMail: clinicalstudies@akceatx.com
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