Elsevier

American Heart Journal

Volume 161, Issue 2, February 2011, Pages 261-268.e2
American Heart Journal

Trial Design
A randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes: Design and rationale of the RADAR Phase IIb trial

https://doi.org/10.1016/j.ahj.2010.10.022Get rights and content

Anticoagulants are the cornerstone of current acute coronary syndrome (ACS) therapy; however, anticoagulation regimens that aggressively reduce ischemic events are almost uniformly associated with more bleeding. REG1, an anticoagulation system, consists of RB006 (pegnivacogin), an RNA oligonucleotide factor IXa inhibitor, and RB007 (anivamersen), its complementary controlling agent. Phase I and IIa studies defined predictable relationships between doses of RB006, RB007, and degree of antifactor IX activity. The efficacy and safety of REG1 for the treatment of patients with ACS managed invasively and the safety of reversing RB006 with RB007 after cardiac catheterization are unknown. Randomized, partially-blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system compared to unfractionated heparin or low molecular heparin in subjects with acute coronary syndrome (RADAR) is designed to assess both the efficacy of the anticoagulant RB006 and the safety of a range of levels of RB006 reversal with RB007. The objectives of RADAR are (1) to determine the safety of a range of levels of RB006 reversal with RB007 after catheterization, (2) to confirm whether a dose of 1 mg/kg RB006 results in near-complete inhibition of factor IXa in patients with ACS, and (3) to assess the efficacy of RB006 as an anticoagulant in patients with ACS undergoing percutaneous coronary intervention.

Section snippets

The REG1 anticoagulation system

REG1 is a novel anticoagulation system made up of an RNA aptamer that binds to and selectively inactivates factor IXa (RB006, pegnivacogin) and its complementary controlling agent (RB007, anivamersen).21

Aptamers are oligonucleotides that bind to proteins based on their three-dimensional structure.22, 23 Because of their nucleotide structure, they typically lack immunogenicity and toxicity, have tunable pharmacokinetics (PK), and can be formulated as either intravenous (IV) or subcutaneous

Clinical experience

The REG1 program has 3 phase I studies assessing the PK and PD of the REG1 system in healthy volunteers and patients with coronary artery disease (CAD).21, 24, 25 A phase II pilot study demonstrated the feasibility of using RB006 as the sole anticoagulant therapy in patients undergoing elective PCI.26 The applicability of these findings to patients with ACS undergoing PCI remains unknown.

The RADAR trial

RADAR (Clinicaltrials.gov identifier NCT00932100) is an international, multicenter, phase II, randomized, partially blinded, active control, clinical trial investigating RB006 and a range of doses of RB007 in patients with ACS managed using an early invasive strategy. The purpose of this article was to describe the design and rationale for the RADAR trial. The authors are solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper

Discussion

RADAR is the first study to address the clinical effectiveness of a drug-controlling agent combination and offers unique challenges in design and interpretation.

RADAR is designed to assess the REG1 system in patients with ACS by addressing 3 critical issues. First, to determine the safety of a range of levels of RB006 reversal with RB007 after catheterization with respect to sheath removal. Second, to confirm whether a dose of 1 mg/kg RB006 results in near-complete inhibition of factor IXa

Conclusions

RADAR is a unique phase II clinical trial investigating a combined anticoagulant thrombotic and complementary active reversal agent. The data from RADAR will answer important questions about each component of the REG1 anticoagulation system and define the best strategy to support the development of adequately powered phase III clinical trials.

Disclosures

Funding: RADAR is funded by Regado Biosciences (Basking Ridge, NJ).

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    • Cited by (0)

    Vladimir Dzavik, MD, served as guest editor for this article.

    RCT reg no. NCT00932100.

    l

    On behalf of the RADAR Investigators. See online Appendix B for a complete listing.

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