Clinical trial NCT02160899: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS-APO(a)Rx in Participants With High Lipoprotein(a)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Elevated Lipoprotein(a)
Keywords: High Lipoprotein(a)
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2014-06-11
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99
timeFrame: Day 85/Day 99
measure: Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)
timeFrame: Up to approximately 32 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Chicoutimi
country: Canada
facility: Chicoutimi Hospital
state: Quebec
city: Quebec
country: Canada
facility: Clinique des Maladies Lipidiques de Quebec Inc.
city: Herlev
country: Denmark
facility: Herlev University Hospital
city: Berlin
country: Germany
facility: Charite - University Hospital Berlin - Campus Virchow - Hospital
city: Koln
country: Germany
facility: Uniklinik Koeln, Zentrum fuer Endokrinologie, Diabetologie und Praeventivmedizin (ZEDP)
city: Magdeburg
country: Germany
facility: Otto-von Guericke Universitaet, Uniklinik Magdeburg
city: Amsterdam
country: Netherlands
facility: University of Amsterdam - Dept. of Vascular Medicine F4-109
city: Maastricht
country: Netherlands
facility: Academic Hospital Maastricht
city: Rotterdam
country: Netherlands
facility: Sint Franciscus Gasthuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Birmingham
country: United Kingdom
facility: Heart of England NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Barlow Medical Centre
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle Upon Tyne Hospitals
Study officials:
References:
citation: 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.
citation: 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.