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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS-APO(a)Rx in Participants With High Lipoprotein(a)

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ClinicalTrials.gov Identifier: NCT02160899
Recruitment Status : Completed
First Posted : June 11, 2014
Results First Posted : December 20, 2019
Last Update Posted : December 20, 2019
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Brief Summary:
The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS-APO(a)Rx given to participants with high lipoprotein(a) for 12 weeks.

Condition or disease Intervention/treatment Phase
Elevated Lipoprotein(a) Drug: ISIS-APO(a)Rx Drug: Placebo Phase 2

Detailed Description:

Lipoprotein(a) [Lp(a)] is a genetic variant of low-density lipoprotein (LDL) in which the apolipoprotein B (apoB) -100 component of LDL is linked by a disulfide bond to apolipoprotein(a) [apo(a)], the distinct protein component of Lp(a) that is mainly responsible for its signature structural and functional properties. Lp(a) is now recognized as an important genetic risk factor for coronary artery disease, stroke and aortic stenosis.

The purpose of this study is to determine if ISIS-APO(a)Rx can reduce the production of apolipoprotein(a), or apo(a). This study will enroll 50 participants with Lipoprotein(a) ≥50 and <175 mg/dL and 10 participants with Lipoprotein(a) ≥175 mg/dL.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind, Placebo-Controlled, Dose Titration, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 494372 Administered Subcutaneously to Patients With High Lipoprotein(a)
Study Start Date : June 2014
Actual Primary Completion Date : November 2015
Actual Study Completion Date : November 2015

Arm Intervention/treatment
Placebo Comparator: Cohort A: Placebo
Participants will receive placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
Drug: Placebo
Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

Experimental: Cohort A: ISIS-APO(a)Rx < 2000 mg
Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Drug: ISIS-APO(a)Rx
ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Other Name: ISIS 494372

Experimental: Cohort A: ISIS-APO(a)Rx >= 2000 mg
Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Drug: ISIS-APO(a)Rx
ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Other Name: ISIS 494372

Placebo Comparator: Cohort B: Placebo
Participants will receive placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
Drug: Placebo
Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

Experimental: Cohort B: ISIS-APO(a)Rx < 2000 mg
Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Drug: ISIS-APO(a)Rx
ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Other Name: ISIS 494372

Experimental: Cohort B: ISIS-APO(a)Rx >= 2000 mg
Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Drug: ISIS-APO(a)Rx
ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
Other Name: ISIS 494372




Primary Outcome Measures :
  1. Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 [ Time Frame: Day 85/Day 99 ]
    Data are reported for evaluable participants.

  2. Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) [ Time Frame: Up to approximately 32 weeks ]
    An adverse event is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or females aged 18-65 inclusive
  • Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved)
  • Males must be surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the participant must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug
  • Body mass index (BMI) ≤40 kg/m2
  • Lipoprotein(a) ≥50 and <175 mg/dL at time of screening (Cohort A)
  • Lipoprotein(a) ≥175 mg/dL at time of screening (Cohort B)

Exclusion Criteria:

  • Clinically significant abnormalities in medical history (e.g., documented previous myocardial infarction, percutaneous coronary intervention (PCI), or major surgery within 3 months of screening, planned surgery that would occur during the study) or physical examination at screening
  • Clinically significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion
  • Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
  • Known history or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
  • Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
  • History of bleeding diathesis or coagulopathy
  • Recent history of, or current drug or alcohol abuse
  • Participant with Lp(a) ≥50 and <175 mg/dL may not receive concomitant niacin therapy during the period 8 weeks prior to screening through the end of the Post-Treatment Evaluation Period
  • Use of statins, ezetimibe or fibrates unless on a stable regimen for at least 8 weeks prior to dosing and will remain on a stable regimen for the duration of the study
  • Use of lipid or Lp(a)-specific apheresis within 4 weeks prior to Screening through the end of the Post-Treatment Evaluation Period
  • Use of concomitant drugs (including herbal or over-the-counter (OTC) medications other than ibuprofen, Benadryl or topical steroids) unless authorized by the Sponsor Medical Monitor
  • Blood donation of 50-499 mL within 30 days of screening or of >499 mL within 8 weeks of screening
  • Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study

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): NCT02160899


Locations
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Canada, Quebec
Chicoutimi Hospital
Chicoutimi, Quebec, Canada, G7H 5H6
Canada
Clinique des Maladies Lipidiques de Quebec Inc.
Quebec, Canada, G1V4M6
Denmark
Herlev University Hospital
Herlev, Denmark, 2730
Germany
Charite - University Hospital Berlin - Campus Virchow - Hospital
Berlin, Germany, 13353
Uniklinik Koeln, Zentrum fuer Endokrinologie, Diabetologie und Praeventivmedizin (ZEDP)
Koln, Germany, 50937
Otto-von Guericke Universitaet, Uniklinik Magdeburg
Magdeburg, Germany, 39120
Netherlands
University of Amsterdam - Dept. of Vascular Medicine F4-109
Amsterdam, Netherlands, 1105 AZ
Academic Hospital Maastricht
Maastricht, Netherlands, 6229 HX
Sint Franciscus Gasthuis
Rotterdam, Netherlands, 3045 PM
University Medical Center Utrecht
Utrecht, Netherlands, 3584 CX
United Kingdom
Heart of England NHS Foundation Trust
Birmingham, United Kingdom, B9 5SS
Barlow Medical Centre
Manchester, United Kingdom, M20 2RN
Newcastle Upon Tyne Hospitals
Newcastle Upon Tyne, United Kingdom, NE1 4LP
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02160899    
Other Study ID Numbers: ISIS 494372-CS3
First Posted: June 11, 2014    Key Record Dates
Results First Posted: December 20, 2019
Last Update Posted: December 20, 2019
Last Verified: December 2019
Keywords provided by Ionis Pharmaceuticals, Inc.:
High Lipoprotein(a)