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Trial record 1 of 1 for:    akcea-apo(a)-Lrx | akcea [Lead] | Phase 2
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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 Description
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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
Elevated Lipoprotein(a) Cardiovascular Disease Drug: ISIS 681257 Drug: Placebo Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
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 : March 7, 2017
Actual Primary Completion Date : July 26, 2018
Actual Study Completion Date : November 13, 2018
Arms and Interventions
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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 Name: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
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 Name: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
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 Name: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
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 Name: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
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 Name: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
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
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Primary Outcome Measures :
  1. Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point [ Time Frame: 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.

  2. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: 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.

  3. Number of Participants With TEAEs by Maximum Severity [ Time Frame: 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.

  4. Number of Participants With TEAEs Leading to Study Discontinuation [ Time Frame: 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 :
  1. Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) [ Time Frame: 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.

  2. Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) [ Time Frame: 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.

  3. Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL [ Time Frame: 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.

  4. Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) [ Time Frame: 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.

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

  6. Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) [ Time Frame: 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:
  1. To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens. [ Time Frame: 6 months ]
    Cmax will be calculated for the treatment groups.

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

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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, or peripheral artery disease
  • Lp(a) plasma level ≥ 60 mg/dL
  • Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors

Key Exclusion Criteria:

  • Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/TIA
  • Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis
  • Heart failure New York Heart Association (NYHA) class IV
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03070782


Locations
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United States, Arizona
Clinical Site
Cottonwood, Arizona, United States, 86326
United States, California
Clinical Site
Huntington Beach, California, United States, 92648
Clinical Site
La Jolla, California, United States, 92103
Clinical Site
Los Angeles, California, United States, 90048
Clinical Site
Stanford, California, United States, 94305
United States, Colorado
Clinical Site
Colorado Springs, Colorado, United States, 80909
United States, Florida
Clinical Site
Boca Raton, Florida, United States, 33434
Clinical Site
Jacksonville, Florida, United States, 32216
United States, Kansas
Clinical Site
Kansas City, Kansas, United States, 66160
United States, Maryland
Clinical Site
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Clinical Site
Boston, Massachusetts, United States, 02114
United States, New York
Clinical Site
Cooperstown, New York, United States, 13326
Clinical Site
New York, New York, United States, 10016
Clinical Site
New York, New York, United States, 10029
United States, Ohio
Clinical Site
Cleveland, Ohio, United States, 44195
United States, Oregon
Clinical Site
Portland, Oregon, United States, 97239
United States, Pennsylvania
Clinical Site
Lancaster, Pennsylvania, United States, 17602
Clinical Site
Philadelphia, Pennsylvania, United States, 19104
United States, Rhode Island
Clinical Site
Providence, Rhode Island, United States, 02906
United States, Texas
Clinical Site
Houston, Texas, United States, 77030
United States, Virginia
Clinical Site
Falls Church, Virginia, United States, 22042
United States, Wisconsin
Clinical Site
Milwaukee, Wisconsin, United States, 53215
Canada, Quebec
Clinical Site
Chicoutimi, Quebec, Canada, G7H7K9
Clinical Site
Montreal, Quebec, Canada, H1T 1C8
Clinical Site
Montréal, Quebec, Canada, H3H 2L9
Clinical Site
Québec, Quebec, Canada, G1V4W2
Canada
Clinical Site
Ottawa, Canada, K1Y4W7
Denmark
Clinical Site
Herlev, Denmark, 2730
Clinical Site
Viborg, Denmark, 8800
Germany
Clinical Site
Berlin, Germany, 13353
Clinical Site
Cologne, Germany, 50937
Netherlands
Clinical Site
Amsterdam, Netherlands, 1105AZ
Sponsors and Collaborators
Akcea Therapeutics
Ionis Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Akcea Therapeutics:
Study Protocol  [PDF] January 25, 2018
Statistical Analysis Plan  [PDF] June 7, 2018

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

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Responsible Party: Akcea Therapeutics
ClinicalTrials.gov Identifier: NCT03070782    
Other Study ID Numbers: ISIS 681257-CS6
2016-003373-18 ( EudraCT Number )
First Posted: March 6, 2017    Key Record Dates
Results First Posted: October 30, 2020
Last Update Posted: October 30, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Akcea Therapeutics:
IONIS-APO(a)-LRx
AKCEA-APO(a)-LRx
Hyperlipoproteinemia(a)
Hyperlipoproteinemia a
Lipoprotein(a)
Lipoprotein a
Lp(a)
 Lp a
Dyslipidemia
Dyslipoproteinemia
Hyperlipidemia
Hyperlipoproteinemia
Lipoprotein
Additional relevant MeSH terms:
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Cardiovascular Diseases
Hyperlipoproteinemias
Hyperlipidemias
 Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases