Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease
Sponsor
Akcea Therapeutics (Industry)
Overall Status
Completed
CT.gov ID
NCT03070782
Collaborator
Ionis Pharmaceuticals, Inc. (Industry)
286
32
6
20.2
8.9
0.4
Study Details
Study Description
Brief Summary
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lipoprotein(a) [Lp(a)] levels in participants with hyperlipoproteinemia(a) and established cardiovascular disease (CVD).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
286 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) Administered Subcutaneously to Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)
Actual Study Start Date
:
Mar 7, 2017
Actual Primary Completion Date
:
Jul 26, 2018
Actual Study Completion Date
:
Nov 13, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort A: ISIS 681257: 20 mg Q4W Cohort A participants received 20 milligrams (mg) ISIS 681257, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses. |
Drug: ISIS 681257
ISIS 681257 solution for SC injection.
Other Names:
|
| Experimental: Cohort B: ISIS 681257: 40 mg Q4W Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses. |
Drug: ISIS 681257
ISIS 681257 solution for SC injection.
Other Names:
|
| Experimental: Cohort C: ISIS 681257: 60 mg Q4W Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses. |
Drug: ISIS 681257
ISIS 681257 solution for SC injection.
Other Names:
|
| Experimental: Cohort D: ISIS 681257: 20 mg Q2W Cohort D participants received 20 mg of ISIS 681257, SC injection, once every 2 weeks (Q2W), for up to 51 weeks and a maximum of 26 doses. |
Drug: ISIS 681257
ISIS 681257 solution for SC injection.
Other Names:
|
| Experimental: Cohort E: ISIS 681257: 20 mg QW Cohort E participants received 20 mg of ISIS 681257, SC injection, once weekly (QW), for up to 52 weeks and a maximum of 52 doses. |
Drug: ISIS 681257
ISIS 681257 solution for SC injection.
Other Names:
|
| Placebo Comparator: Placebo Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257). |
Drug: Placebo
Sterile normal saline (0.9% NaCl)
|
Outcome Measures
Primary Outcome Measures
- Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
An ANCOVA model was performed on the log ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline - 1) × 100.
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Up to 16 weeks post treatment period (up to approximately 1.3 years)]
An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study.
- Number of Participants With TEAEs by Maximum Severity [Up to 16 weeks post treatment period (up to approximately 1.3 years)]
An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. The severity of TEAEs was assessed based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. TEAEs were graded on a 5-point scale where 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Potentially life-threatening and 5 = Death.
- Number of Participants With TEAEs Leading to Study Discontinuation [Up to 16 weeks post treatment period (up to approximately 1.3 years)]
An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAE was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study.
Secondary Outcome Measures
- Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
An ANCOVA model was performed on the log ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline - 1) × 100.
- Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
The percentage of participants who achieved ≤ 125 nmol/L or ≤ 50 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate.
- Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
The percentage of participants who achieved ≤ 75 nmol/L or ≤ 30 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate.
- Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
An ANCOVA model was performed on the log ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline - 1) × 100.
- Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
An ANCOVA model was performed on the log ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline - 1) × 100.
- Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) [Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)]
An ANCOVA model was performed on the log ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline - 1) × 100.
Other Outcome Measures
- To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens. [6 months]
Cmax will be calculated for the treatment groups.
- To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens. [6 months]
Tmax will be calculated for the treatment groups.
- To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens. [6 months]
AUC values will be calculated for the treatment groups.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 80 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Key Inclusion Criteria:
-
Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, or peripheral artery disease
-
Lp(a) plasma level ≥ 60 mg/dL
-
Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors
Key Exclusion Criteria:
-
Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/TIA
-
Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis
-
Heart failure New York Heart Association (NYHA) class IV
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Clinical Site | Cottonwood | Arizona | United States | 86326 |
| 2 | Clinical Site | Huntington Beach | California | United States | 92648 |
| 3 | Clinical Site | La Jolla | California | United States | 92103 |
| 4 | Clinical Site | Los Angeles | California | United States | 90048 |
| 5 | Clinical Site | Stanford | California | United States | 94305 |
| 6 | Clinical Site | Colorado Springs | Colorado | United States | 80909 |
| 7 | Clinical Site | Boca Raton | Florida | United States | 33434 |
| 8 | Clinical Site | Jacksonville | Florida | United States | 32216 |
| 9 | Clinical Site | Kansas City | Kansas | United States | 66160 |
| 10 | Clinical Site | Baltimore | Maryland | United States | 21201 |
| 11 | Clinical Site | Boston | Massachusetts | United States | 02114 |
| 12 | Clinical Site | Cooperstown | New York | United States | 13326 |
| 13 | Clinical Site | New York | New York | United States | 10016 |
| 14 | Clinical Site | New York | New York | United States | 10029 |
| 15 | Clinical Site | Cleveland | Ohio | United States | 44195 |
| 16 | Clinical Site | Portland | Oregon | United States | 97239 |
| 17 | Clinical Site | Lancaster | Pennsylvania | United States | 17602 |
| 18 | Clinical Site | Philadelphia | Pennsylvania | United States | 19104 |
| 19 | Clinical Site | Providence | Rhode Island | United States | 02906 |
| 20 | Clinical Site | Houston | Texas | United States | 77030 |
| 21 | Clinical Site | Falls Church | Virginia | United States | 22042 |
| 22 | Clinical Site | Milwaukee | Wisconsin | United States | 53215 |
| 23 | Clinical Site | Chicoutimi | Quebec | Canada | G7H7K9 |
| 24 | Clinical Site | Montreal | Quebec | Canada | H1T 1C8 |
| 25 | Clinical Site | Montréal | Quebec | Canada | H3H 2L9 |
| 26 | Clinical Site | Québec | Quebec | Canada | G1V4W2 |
| 27 | Clinical Site | Ottawa | Canada | K1Y4W7 | |
| 28 | Clinical Site | Herlev | Denmark | 2730 | |
| 29 | Clinical Site | Viborg | Denmark | 8800 | |
| 30 | Clinical Site | Berlin | Germany | 13353 | |
| 31 | Clinical Site | Cologne | Germany | 50937 | |
| 32 | Clinical Site | Amsterdam | Netherlands | 1105AZ |
Sponsors and Collaborators
- Akcea Therapeutics
- Ionis Pharmaceuticals, Inc.
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Akcea Therapeutics
ClinicalTrials.gov Identifier:
NCT03070782
Other Study ID Numbers:
- ISIS 681257-CS6
- 2016-003373-18
First Posted:
Mar 6, 2017
Last Update Posted:
Oct 30, 2020
Last Verified:
Oct 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Akcea Therapeutics
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Participants with a clinical diagnosis of hyperlipoproteinemia(a) and established CVD were enrolled in 31 study centers in United States, Canada, Denmark, Germany and Netherlands between 7th March 2017 to 13th November 2018. |
|---|---|
| Pre-assignment Detail | 286 participants were randomized in a 1:1:1:1:1 ratio to Cohorts A, B, C, D or E. In each cohort, participants were randomized in a 5:1 ratio to receive ISIS 681257 or placebo. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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 | 41 | 47 | 43 | 43 | 36 | 40 |
| NOT COMPLETED | 7 | 1 | 4 | 5 | 12 | 7 |
Baseline Characteristics
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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 Participants | 48 | 48 | 47 | 48 | 48 | 47 | 286 |
| Age (years) [Mean (Full Range) ] | |||||||
| Mean (Full Range) [years] |
60.0
|
61.3
|
62.2
|
57.9
|
58.9
|
59.9
|
60.0
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
19
39.6%
|
12
25%
|
14
29.8%
|
17
35.4%
|
20
41.7%
|
15
31.9%
|
97
33.9%
|
| Male |
29
60.4%
|
36
75%
|
33
70.2%
|
31
64.6%
|
28
58.3%
|
32
68.1%
|
189
66.1%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||||
| Hispanic or Latino |
2
4.2%
|
1
2.1%
|
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%
|
48
100%
|
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%
|
| Race (NIH/OMB) (Count of Participants) | |||||||
| American Indian or Alaska Native |
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%
|
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%
|
| Black or African American |
2
4.2%
|
3
6.3%
|
0
0%
|
0
0%
|
1
2.1%
|
0
0%
|
6
2.1%
|
| White |
44
91.7%
|
45
93.8%
|
47
100%
|
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%
|
| Unknown or Not Reported |
1
2.1%
|
0
0%
|
0
0%
|
1
2.1%
|
0
0%
|
0
0%
|
2
0.7%
|
Outcome Measures
| Title | Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point |
|---|---|
| Description | An ANCOVA model was performed on the log ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline - 1) × 100. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible intent-to-treat (ITT) population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Geometric Mean (95% Confidence Interval) [percent change] |
-35
|
-56
|
-72
|
-58
|
-80
|
-6
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0032 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -31 | |
| Confidence Interval |
(2-Sided) 95% -46 to -12 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -54 | |
| Confidence Interval |
(2-Sided) 95% -64 to -41 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -70 | |
| Confidence Interval |
(2-Sided) 95% -77 to -62 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -56 | |
| Confidence Interval |
(2-Sided) 95% -65 to -43 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -78 | |
| Confidence Interval |
(2-Sided) 95% -83 to -72 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
| Title | Number of Participants With Treatment Emergent Adverse Events (TEAEs) |
|---|---|
| Description | An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. |
| Time Frame | Up to 16 weeks post treatment period (up to approximately 1.3 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Count of Participants [Participants] |
46
95.8%
|
43
89.6%
|
43
91.5%
|
41
85.4%
|
44
91.7%
|
41
87.2%
|
| Title | Number of Participants With TEAEs by Maximum Severity |
|---|---|
| Description | An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. The severity of TEAEs was assessed based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. TEAEs were graded on a 5-point scale where 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Potentially life-threatening and 5 = Death. |
| Time Frame | Up to 16 weeks post treatment period (up to approximately 1.3 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). Only participants with at least one TEAE were analyzed for this outcome measure. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 46 | 43 | 43 | 41 | 44 | 41 |
| Mild |
20
41.7%
|
21
43.8%
|
16
34%
|
24
50%
|
21
43.8%
|
22
46.8%
|
| Moderate |
20
41.7%
|
19
39.6%
|
21
44.7%
|
15
31.3%
|
20
41.7%
|
16
34%
|
| Severe |
6
12.5%
|
3
6.3%
|
6
12.8%
|
2
4.2%
|
3
6.3%
|
3
6.4%
|
| Title | Number of Participants With TEAEs Leading to Study Discontinuation |
|---|---|
| Description | An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAE was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. |
| Time Frame | Up to 16 weeks post treatment period (up to approximately 1.3 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Count of Participants [Participants] |
3
6.3%
|
0
0%
|
3
6.4%
|
1
2.1%
|
6
12.5%
|
2
4.3%
|
| Title | Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) |
|---|---|
| Description | An ANCOVA model was performed on the log ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline - 1) × 100. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Geometric Mean (95% Confidence Interval) [percent change] |
-7
|
-26
|
-16
|
-17
|
-23
|
-1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4407 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -6 | |
| Confidence Interval |
(2-Sided) 95% -19 to 9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -25 | |
| Confidence Interval |
(2-Sided) 95% -35 to -13 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0368 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -14 | |
| Confidence Interval |
(2-Sided) 95% -26 to -1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0216 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -16 | |
| Confidence Interval |
(2-Sided) 95% -28 to -3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0012 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -22 | |
| Confidence Interval |
(2-Sided) 95% -33 to -9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
| Title | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) |
|---|---|
| Description | The percentage of participants who achieved ≤ 125 nmol/L or ≤ 50 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Number [percentage of participants] |
22.9
47.7%
|
62.5
130.2%
|
80.9
172.1%
|
64.6
134.6%
|
97.9
204%
|
6.4
13.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0286 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 4.98 | |
| Confidence Interval |
(2-Sided) 95% 1.2 to 21.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 31.07 | |
| Confidence Interval |
(2-Sided) 95% 7.3 to 131.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 122.81 | |
| Confidence Interval |
(2-Sided) 95% 24.0 to 627.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 43.78 | |
| Confidence Interval |
(2-Sided) 95% 9.8 to 195.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1124.56 | |
| Confidence Interval |
(2-Sided) 95% 109.3 to 11571 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL |
|---|---|
| Description | The percentage of participants who achieved ≤ 75 nmol/L or ≤ 30 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Number [percentage of participants] |
6.3
13.1%
|
25.0
52.1%
|
53.2
113.2%
|
33.3
69.4%
|
70.8
147.5%
|
0
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2007 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 7.34 | |
| Confidence Interval |
(2-Sided) 95% 0.3 to 155.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0258 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 27.92 | |
| Confidence Interval |
(2-Sided) 95% 1.5 to 521.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0014 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 113.92 | |
| Confidence Interval |
(2-Sided) 95% 6.2 to 2098.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0063 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 59.85 | |
| Confidence Interval |
(2-Sided) 95% 3.2 to 1128.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 347.02 | |
| Confidence Interval |
(2-Sided) 95% 18.3 to 6597.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) |
|---|---|
| Description | An ANCOVA model was performed on the log ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline - 1) × 100. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Geometric Mean (95% Confidence Interval) [percent change] |
-3
|
-15
|
-8
|
-9
|
-16
|
1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4022 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -4 | |
| Confidence Interval |
(2-Sided) 95% -12 to 5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -16 | |
| Confidence Interval |
(2-Sided) 95% -23 to -9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0323 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -9 | |
| Confidence Interval |
(2-Sided) 95% -17 to -1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0157 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -10 | |
| Confidence Interval |
(2-Sided) 95% -18 to -2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -17 | |
| Confidence Interval |
(2-Sided) 95% -24 to -9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
| Title | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] |
|---|---|
| Description | An ANCOVA model was performed on the log ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline - 1) × 100. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Geometric Mean (95% Confidence Interval) [percent change] |
-28
|
-49
|
-63
|
-45
|
-70
|
-20
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4956 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -9 | |
| Confidence Interval |
(2-Sided) 95% -32 to 21 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0027 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -36 | |
| Confidence Interval |
(2-Sided) 95% -52 to -14 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -54 | |
| Confidence Interval |
(2-Sided) 95% -65 to -38 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0114 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -31 | |
| Confidence Interval |
(2-Sided) 95% -48 to -8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -62 | |
| Confidence Interval |
(2-Sided) 95% -72 to -49 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
| Title | Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) |
|---|---|
| Description | An ANCOVA model was performed on the log ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline - 1) × 100. |
| Time Frame | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). FAS represented the practically feasible ITT population as delineated in ICH Guideline E9. |
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo |
|---|---|---|---|---|---|---|
| Arm/Group Description | Cohort A participants received 20 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). |
| Measure Participants | 48 | 48 | 47 | 48 | 48 | 47 |
| Geometric Mean (95% Confidence Interval) [percent change] |
-37
|
-57
|
-79
|
-64
|
-88
|
14
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cohort A: ISIS 681257: 20 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0020 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -45 | |
| Confidence Interval |
(2-Sided) 95% -62 to -19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Cohort B: ISIS 681257: 40 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -63 | |
| Confidence Interval |
(2-Sided) 95% -74 to -46 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Cohort C: ISIS 681257: 60 mg Q4W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -82 | |
| Confidence Interval |
(2-Sided) 95% -87 to -73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Cohort D: ISIS 681257: 20 mg Q2W, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -68 | |
| Confidence Interval |
(2-Sided) 95% -78 to -54 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Cohort E: ISIS 681257: 20 mg QW, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference in % CFB |
| Estimated Value | -89 | |
| Confidence Interval |
(2-Sided) 95% -93 to -84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Mean difference in percent (%) change from baseline (CFB) based on difference in LSM of log (Primary Analysis Time Point/Baseline) was estimated. | |
| Title | To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens. |
|---|---|
| Description | Cmax will be calculated for the treatment groups. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens. |
|---|---|
| Description | Tmax will be calculated for the treatment groups. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens. |
|---|---|
| Description | AUC values will be calculated for the treatment groups. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | Up to 16 weeks post-treatment period (up to approximately 1.3 years) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Safety Set included all participants who were randomized and received at least 1 dose of study drug (ISIS 681257 or placebo). | |||||||||||
| Arm/Group Title | Cohort A: ISIS 681257: 20 mg Q4W | Cohort B: ISIS 681257: 40 mg Q4W | Cohort C: ISIS 681257: 60 mg Q4W | Cohort D: ISIS 681257: 20 mg Q2W | Cohort E: ISIS 681257: 20 mg QW | Placebo | ||||||
| Arm/Group Description | Cohort A participants received 20 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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/48 (14.6%) | 7/48 (14.6%) | 7/47 (14.9%) | 3/48 (6.3%) | 4/48 (8.3%) | 3/47 (6.4%) | ||||||
| Cardiac disorders | ||||||||||||
| Acute myocardial infarction | 2/48 (4.2%) | 0/48 (0%) | 1/47 (2.1%) | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Angina unstable | 1/48 (2.1%) | 0/48 (0%) | 1/47 (2.1%) | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Angina pectoris | 1/48 (2.1%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | ||||||
| Coronary artery disease | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Ventricular tachycardia | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Oesophagitis haemorrhagic | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Pancreatitis acute | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | ||||||
| General disorders | ||||||||||||
| Malaise | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Non-cardiac chest pain | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Cyst | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | ||||||
| Infections and infestations | ||||||||||||
| Pneumonia | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Upper respiratory tract infection | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Ankle fracture | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Joint dislocation | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Lower limb fracture | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Radius fracture | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Road traffic accident | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Gastrointestinal anastomotic stenosis | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Gout | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Myalgia | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Lung neoplasm | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Lung neoplasm malignant | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Nervous system disorders | ||||||||||||
| Syncope | 1/48 (2.1%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Ischaemic stroke | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | ||||||
| Psychiatric disorders | ||||||||||||
| Acute psychosis | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Depression | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Reproductive system and breast disorders | ||||||||||||
| Vaginal haemorrhage | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
| Surgical and medical procedures | ||||||||||||
| Open reduction of fracture | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Vascular disorders | ||||||||||||
| Hypertensive crisis | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | ||||||
Other (Not Including 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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 38/48 (79.2%) | 42/48 (87.5%) | 40/47 (85.1%) | 36/48 (75%) | 42/48 (87.5%) | 36/47 (76.6%) | ||||||
| Cardiac disorders | ||||||||||||
| Angina pectoris | 8/48 (16.7%) | 3/48 (6.3%) | 2/47 (4.3%) | 1/48 (2.1%) | 2/48 (4.2%) | 1/47 (2.1%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Diarrhoea | 5/48 (10.4%) | 3/48 (6.3%) | 2/47 (4.3%) | 3/48 (6.3%) | 5/48 (10.4%) | 3/47 (6.4%) | ||||||
| Nausea | 3/48 (6.3%) | 3/48 (6.3%) | 3/47 (6.4%) | 0/48 (0%) | 2/48 (4.2%) | 1/47 (2.1%) | ||||||
| Vomiting | 1/48 (2.1%) | 3/48 (6.3%) | 2/47 (4.3%) | 3/48 (6.3%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| General disorders | ||||||||||||
| Injection site erythema | 3/48 (6.3%) | 13/48 (27.1%) | 13/47 (27.7%) | 11/48 (22.9%) | 22/48 (45.8%) | 0/47 (0%) | ||||||
| Fatigue | 8/48 (16.7%) | 7/48 (14.6%) | 2/47 (4.3%) | 1/48 (2.1%) | 3/48 (6.3%) | 1/47 (2.1%) | ||||||
| Injection site pain | 2/48 (4.2%) | 2/48 (4.2%) | 3/47 (6.4%) | 1/48 (2.1%) | 3/48 (6.3%) | 0/47 (0%) | ||||||
| Influenza like illness | 3/48 (6.3%) | 2/48 (4.2%) | 4/47 (8.5%) | 1/48 (2.1%) | 0/48 (0%) | 2/47 (4.3%) | ||||||
| Injection site pruritus | 1/48 (2.1%) | 4/48 (8.3%) | 1/47 (2.1%) | 2/48 (4.2%) | 2/48 (4.2%) | 0/47 (0%) | ||||||
| Oedema peripheral | 1/48 (2.1%) | 2/48 (4.2%) | 2/47 (4.3%) | 2/48 (4.2%) | 0/48 (0%) | 4/47 (8.5%) | ||||||
| Pyrexia | 0/48 (0%) | 3/48 (6.3%) | 1/47 (2.1%) | 0/48 (0%) | 2/48 (4.2%) | 3/47 (6.4%) | ||||||
| Injection site bruising | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 0/48 (0%) | 4/48 (8.3%) | 0/47 (0%) | ||||||
| Immune system disorders | ||||||||||||
| Seasonal allergy | 0/48 (0%) | 1/48 (2.1%) | 2/47 (4.3%) | 1/48 (2.1%) | 2/48 (4.2%) | 3/47 (6.4%) | ||||||
| Infections and infestations | ||||||||||||
| Viral upper respiratory tract infection | 8/48 (16.7%) | 10/48 (20.8%) | 8/47 (17%) | 8/48 (16.7%) | 15/48 (31.3%) | 11/47 (23.4%) | ||||||
| Urinary tract infection | 7/48 (14.6%) | 7/48 (14.6%) | 10/47 (21.3%) | 6/48 (12.5%) | 9/48 (18.8%) | 3/47 (6.4%) | ||||||
| Sinusitis | 2/48 (4.2%) | 2/48 (4.2%) | 4/47 (8.5%) | 4/48 (8.3%) | 3/48 (6.3%) | 3/47 (6.4%) | ||||||
| Upper respiratory tract infection | 4/48 (8.3%) | 3/48 (6.3%) | 0/47 (0%) | 3/48 (6.3%) | 4/48 (8.3%) | 5/47 (10.6%) | ||||||
| Influenza | 5/48 (10.4%) | 0/48 (0%) | 2/47 (4.3%) | 2/48 (4.2%) | 5/48 (10.4%) | 1/47 (2.1%) | ||||||
| Gastroenteritis | 2/48 (4.2%) | 1/48 (2.1%) | 1/47 (2.1%) | 2/48 (4.2%) | 4/48 (8.3%) | 3/47 (6.4%) | ||||||
| Bronchitis | 1/48 (2.1%) | 0/48 (0%) | 2/47 (4.3%) | 2/48 (4.2%) | 0/48 (0%) | 3/47 (6.4%) | ||||||
| Conjunctivitis | 0/48 (0%) | 0/48 (0%) | 0/47 (0%) | 3/48 (6.3%) | 1/48 (2.1%) | 0/47 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Contusion | 2/48 (4.2%) | 0/48 (0%) | 1/47 (2.1%) | 3/48 (6.3%) | 3/48 (6.3%) | 0/47 (0%) | ||||||
| Fall | 2/48 (4.2%) | 3/48 (6.3%) | 0/47 (0%) | 1/48 (2.1%) | 2/48 (4.2%) | 0/47 (0%) | ||||||
| Investigations | ||||||||||||
| Blood creatine phosphokinase increased | 5/48 (10.4%) | 1/48 (2.1%) | 1/47 (2.1%) | 3/48 (6.3%) | 3/48 (6.3%) | 2/47 (4.3%) | ||||||
| Blood bilirubin increased | 1/48 (2.1%) | 0/48 (0%) | 2/47 (4.3%) | 2/48 (4.2%) | 5/48 (10.4%) | 3/47 (6.4%) | ||||||
| Laboratory test abnormal | 3/48 (6.3%) | 1/48 (2.1%) | 1/47 (2.1%) | 3/48 (6.3%) | 1/48 (2.1%) | 1/47 (2.1%) | ||||||
| Alanine aminotransferase increased | 2/48 (4.2%) | 1/48 (2.1%) | 0/47 (0%) | 1/48 (2.1%) | 3/48 (6.3%) | 0/47 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Myalgia | 4/48 (8.3%) | 5/48 (10.4%) | 10/47 (21.3%) | 6/48 (12.5%) | 3/48 (6.3%) | 5/47 (10.6%) | ||||||
| Arthralgia | 1/48 (2.1%) | 5/48 (10.4%) | 4/47 (8.5%) | 2/48 (4.2%) | 4/48 (8.3%) | 2/47 (4.3%) | ||||||
| Back pain | 2/48 (4.2%) | 7/48 (14.6%) | 2/47 (4.3%) | 1/48 (2.1%) | 4/48 (8.3%) | 3/47 (6.4%) | ||||||
| Pain in extremity | 4/48 (8.3%) | 2/48 (4.2%) | 3/47 (6.4%) | 1/48 (2.1%) | 3/48 (6.3%) | 1/47 (2.1%) | ||||||
| Neck pain | 1/48 (2.1%) | 1/48 (2.1%) | 4/47 (8.5%) | 3/48 (6.3%) | 1/48 (2.1%) | 1/47 (2.1%) | ||||||
| Muscle spasms | 3/48 (6.3%) | 1/48 (2.1%) | 0/47 (0%) | 2/48 (4.2%) | 3/48 (6.3%) | 2/47 (4.3%) | ||||||
| Musculoskeletal pain | 1/48 (2.1%) | 3/48 (6.3%) | 0/47 (0%) | 1/48 (2.1%) | 1/48 (2.1%) | 2/47 (4.3%) | ||||||
| Musculoskeletal stiffness | 0/48 (0%) | 0/48 (0%) | 1/47 (2.1%) | 0/48 (0%) | 3/48 (6.3%) | 0/47 (0%) | ||||||
| Flank pain | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 0/48 (0%) | 3/47 (6.4%) | ||||||
| Nervous system disorders | ||||||||||||
| Headache | 6/48 (12.5%) | 7/48 (14.6%) | 4/47 (8.5%) | 4/48 (8.3%) | 6/48 (12.5%) | 5/47 (10.6%) | ||||||
| Dizziness | 4/48 (8.3%) | 3/48 (6.3%) | 4/47 (8.5%) | 2/48 (4.2%) | 4/48 (8.3%) | 2/47 (4.3%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Cough | 2/48 (4.2%) | 3/48 (6.3%) | 3/47 (6.4%) | 2/48 (4.2%) | 6/48 (12.5%) | 5/47 (10.6%) | ||||||
| Oropharyngeal pain | 3/48 (6.3%) | 3/48 (6.3%) | 4/47 (8.5%) | 1/48 (2.1%) | 5/48 (10.4%) | 1/47 (2.1%) | ||||||
| Dyspnoea | 2/48 (4.2%) | 5/48 (10.4%) | 0/47 (0%) | 1/48 (2.1%) | 3/48 (6.3%) | 2/47 (4.3%) | ||||||
| Rhinorrhoea | 3/48 (6.3%) | 0/48 (0%) | 1/47 (2.1%) | 1/48 (2.1%) | 2/48 (4.2%) | 1/47 (2.1%) | ||||||
| Nasal congestion | 1/48 (2.1%) | 3/48 (6.3%) | 0/47 (0%) | 0/48 (0%) | 1/48 (2.1%) | 2/47 (4.3%) | ||||||
| Epistaxis | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 2/48 (4.2%) | 1/48 (2.1%) | 4/47 (8.5%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Dermatitis | 0/48 (0%) | 1/48 (2.1%) | 0/47 (0%) | 0/48 (0%) | 3/48 (6.3%) | 1/47 (2.1%) | ||||||
| Vascular disorders | ||||||||||||
| Hypertension | 3/48 (6.3%) | 1/48 (2.1%) | 3/47 (6.4%) | 4/48 (8.3%) | 4/48 (8.3%) | 2/47 (4.3%) | ||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Akcea Therapeutics |
| Phone | 617-207-0289 |
| clinicalstudies@akceatx.com |
Responsible Party:
Akcea Therapeutics
ClinicalTrials.gov Identifier:
NCT03070782
Other Study ID Numbers:
- ISIS 681257-CS6
- 2016-003373-18
First Posted:
Mar 6, 2017
Last Update Posted:
Oct 30, 2020
Last Verified:
Oct 1, 2020