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

NCT ID: NCT02160899

Last Updated: 2019-12-20

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

64 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-06-30

Study Completion Date

2015-11-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Elevated Lipoprotein(a)

Keywords

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High Lipoprotein(a)

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

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.

Group Type EXPERIMENTAL

ISIS-APO(a)Rx

Intervention Type DRUG

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.

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.

Group Type EXPERIMENTAL

ISIS-APO(a)Rx

Intervention Type DRUG

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.

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

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.

Group Type EXPERIMENTAL

ISIS-APO(a)Rx

Intervention Type DRUG

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.

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.

Group Type EXPERIMENTAL

ISIS-APO(a)Rx

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type DRUG

Placebo

Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

Intervention Type DRUG

Other Intervention Names

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ISIS 494372

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Chicoutimi Hospital

Chicoutimi, Quebec, Canada

Site Status

Clinique des Maladies Lipidiques de Quebec Inc.

Québec, , Canada

Site Status

Herlev University Hospital

Herlev, , Denmark

Site Status

Charite - University Hospital Berlin - Campus Virchow - Hospital

Berlin, , Germany

Site Status

Uniklinik Koeln, Zentrum fuer Endokrinologie, Diabetologie und Praeventivmedizin (ZEDP)

Cologne, , Germany

Site Status

Otto-von Guericke Universitaet, Uniklinik Magdeburg

Magdeburg, , Germany

Site Status

University of Amsterdam - Dept. of Vascular Medicine F4-109

Amsterdam, , Netherlands

Site Status

Academic Hospital Maastricht

Maastricht, , Netherlands

Site Status

Sint Franciscus Gasthuis

Rotterdam, , Netherlands

Site Status

University Medical Center Utrecht

Utrecht, , Netherlands

Site Status

Heart of England NHS Foundation Trust

Birmingham, , United Kingdom

Site Status

Barlow Medical Centre

Manchester, , United Kingdom

Site Status

Newcastle Upon Tyne Hospitals

Newcastle upon Tyne, , United Kingdom

Site Status

Countries

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Canada Denmark Germany Netherlands United Kingdom

References

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Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke ST, Witztum JL, Stroes ES, Tsimikas S. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016 Nov 5;388(10057):2239-2253. doi: 10.1016/S0140-6736(16)31009-1. Epub 2016 Sep 21.

Reference Type DERIVED
PMID: 27665230 (View on PubMed)

Tragante V, Asselbergs FW, Swerdlow DI, Palmer TM, Moore JH, de Bakker PIW, Keating BJ, Holmes MV. Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk. Hum Genet. 2016 May;135(5):453-467. doi: 10.1007/s00439-016-1647-9. Epub 2016 Mar 5.

Reference Type DERIVED
PMID: 26946290 (View on PubMed)

Other Identifiers

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ISIS 494372-CS3

Identifier Type: -

Identifier Source: org_study_id