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Trial record 1 of 1 for:    ISIS-APO(a)Rx
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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS-APO(a)Rx in Patients With High Lipoprotein(a)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02160899
First received: June 5, 2014
Last updated: December 2, 2015
Last verified: December 2015
  Purpose
The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS-APO(a)Rx given to patients with high lipoprotein(a) for 12 weeks.

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

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
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)

Further study details as provided by Ionis Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • The safety of ISIS 494372 will be assessed by determining the incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters. [ Time Frame: Weekly for 32 weeks ]

    To characterize the safety of ISIS-APO(a)Rx in individual patients at escalating doses of 100, 200, and 300 mg/week.

    Results in patients dosed with ISIS 494372 will be compared with those from patients dosed with placebo.


  • The tolerability of ISIS 494372 will be assessed by determining the incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters. [ Time Frame: Weekly for 32 weeks ]

    To characterize the tolerability of ISIS-APO(a)Rx in individual patients at escalating doses of 100, 200, and 300 mg/week.

    Results in patients dosed with ISIS 494372 will be compared with those from patients dosed with placebo.


  • To characterize the efficacy of ISIS-APO(a)Rx, changes inserum Lp(a) levels will be assessed following SC administration of ISIS 494372 and compared to placebo. [ Time Frame: End of study at week 32 ]
    To characterize the efficacy of ISIS-APO(a)Rx in lowering Lp(a) using a dose titration study design


Secondary Outcome Measures:
  • Pharmacodynamic effects of ISIS-APO(a)Rx [ Time Frame: End of study at week 32 ]
    To determine the pharmacodynamic effects of ISIS-APO(a)Rx, changes in levels of oxidized phospholipids associated with apoB-100, Lp-PLA2, lipoprotein(a) isoform size, lipid panel, systemic markers of inflammation, and plasminogen/coagulation markers will be assessed following SC administration of ISIS 494372 and compared to placebo.


Enrollment: 65
Study Start Date: June 2014
Study Completion Date: November 2015
Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ISIS-APO(a)Rx
Drug: ISIS-APO(a)Rx Once-weekly dose administered subcutaneously of ISIS-APO(a)Rx from Day 1 to Day 78. Patients will receive 100 mg of ISIS-APO(a)Rx on Days 1, 8, 15, 22. Patients will receive 200 mg of ISIS-APO(a)Rx on Days 29, 36, 43, 50 unless down titrated. Patients will then receive 300 mg of ISIS-APO(a)Rx on Days 57, 64, 71, 78 unless down titrated.
Drug: ISIS-APO(a)Rx
Placebo Comparator: Placebo (Normal Saline)
Drug: Placebo (Normal Saline) Once-weekly dose administered subcutaneously of Placebo from Day 1 to Day 78. Patients will receive 100 mg Placebo on Days 1, 8, 15, 22. Patients will receive 200 mg Placebo on Days 29, 36, 43, 50 unless down titrated. Patients will then receive 300 mg Placebo on Days 57, 64, 71, 78 unless down titrated
Drug: Placebo

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 patients with Lipoprotein(a) ≥50 and <175 mg/dL and 10 patients with Lipoprotein(a) ≥175 mg/dL.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (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 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 patient 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
  • 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, 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 patient 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
  • Patients 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 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 patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02160899

Locations
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.
Investigators
Principal Investigator: Daniel Gaudet, MD ECOGENE-21 Clinical Trial Center - Chicoutimi Hospital
Principal Investigator: Jean Bergeron, MD Clinique des Maladies Lipidiques de Quebec Inc.
Principal Investigator: Borge Nordestgaard, MD University of Copenhagen
Principal Investigator: Ioanna Gouni-Berthold, MD Uniklinik Koeln, Zentrum fuer Endokrinologie, Diabetologie und Praeventivmedizin (ZEDP)
Principal Investigator: Hartmut Schmidt, MD University Hospital of Muenster, KMT Center
Principal Investigator: Elisabeth Steinhagen-Thiessen, MD Charite - University Hospital Berlin - Campus Virchow - Hospital
Principal Investigator: Berend Isermann, MD Otto-von Guericke Universitaet, Uniklinik Magdeburg
Principal Investigator: A Liem, MD Sint Franciscus Gasthuis
Principal Investigator: Frank L.J. Visseren, MD UMC Utrecht
Principal Investigator: Erik Stroes, MD University of Amsterdam - Dept. of Vascular Medicine F4-109
Principal Investigator: Abraham Anthonie Kroon, MD Maastricht University Medical Center
Principal Investigator: Dermot Neely, MD Newcastle Upon Tyne Hospitals
Principal Investigator: Handrean Soran, MD Barlow Medical Centre
Principal Investigator: Alan Jones, MD Heart of England NHS Foundation Trust
Principal Investigator: Niels Riksen, MD Radboudumc Nijmegen