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

NCT02160899 | Completed Phase 2 Results

• 1 other identifier: ISIS 494372-CS3
• Study Type: interventional
• Target: 64
• Locations: 5 countries
• Sites: 13

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.

Conditions

Elevated Lipoprotein(a)

Keywords

High Lipoprotein(a)

Outcome Measures

Primary Outcomes (2)

• Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99

  Data are reported for evaluable participants.

  Day 85/Day 99

• Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)

  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.

  Up to approximately 32 weeks

Study Arms (6)

Cohort A: Placebo

PLACEBO COMPARATOR

Participants will receive placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

Drug: Placebo

Cohort A: ISIS-APO(a)Rx < 2000 mg

EXPERIMENTAL

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

Cohort A: ISIS-APO(a)Rx >= 2000 mg

EXPERIMENTAL

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

Cohort B: Placebo

PLACEBO COMPARATOR

Participants will receive placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

Drug: Placebo

Cohort B: ISIS-APO(a)Rx < 2000 mg

EXPERIMENTAL

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

Cohort B: ISIS-APO(a)Rx >= 2000 mg

EXPERIMENTAL

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

Interventions

ISIS-APO(a)Rx 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.

Also known as: ISIS 494372

Cohort A: ISIS-APO(a)Rx < 2000 mg; Cohort A: ISIS-APO(a)Rx >= 2000 mg; Cohort B: ISIS-APO(a)Rx < 2000 mg; Cohort B: ISIS-APO(a)Rx >= 2000 mg

Placebo DRUG

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

Cohort A: Placebo; Cohort B: Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (13)

Chicoutimi Hospital

Chicoutimi, Quebec, G7H 5H6, Canada

Location

Clinique des Maladies Lipidiques de Quebec Inc.

Québec, G1V4M6, Canada

Location

Herlev University Hospital

Herlev, 2730, Denmark

Location

Charite - University Hospital Berlin - Campus Virchow - Hospital

Berlin, 13353, Germany

Location

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

Cologne, 50937, Germany

Location

Otto-von Guericke Universitaet, Uniklinik Magdeburg

Magdeburg, 39120, Germany

Location

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

Amsterdam, 1105 AZ, Netherlands

Location

Academic Hospital Maastricht

Maastricht, 6229 HX, Netherlands

Location

Sint Franciscus Gasthuis

Rotterdam, 3045 PM, Netherlands

Location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Heart of England NHS Foundation Trust

Birmingham, B9 5SS, United Kingdom

Location

Barlow Medical Centre

Manchester, M20 2RN, United Kingdom

Location

Newcastle Upon Tyne Hospitals

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 27665230 DERIVED

• 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.

  PMID: 26946290 DERIVED

MeSH Terms

Interventions

ISIS-APO(a)Rx

Results Point of Contact

• Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.

patients@ionisph.com

800-679-4747

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2014
• First Posted: June 11, 2014
• Study Start: June 1, 2014
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: December 20, 2019
• Results First Posted: December 20, 2019

Record last verified: 2019-12

Locations

DE (3); GB (3); CA (2); DK (1); NL (4)