Absence of QTc prolongation with betrixaban: a randomized, double-blind, placebo- and positive-controlled thorough ECG study

Abstract

Objective: To evaluate the effects of the anticoagulant betrixaban on individual heart rate-corrected QT (QTcI).

Research design and methods: Ninety-six healthy adults were randomly assigned to single-dose betrixaban 80 and 140 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin 400 mg (positive control) in a four-period crossover study. Electrocardiograms were recorded at pre-dose and post-dose hours 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24.

Main outcomes measures: An analysis of covariance determined the placebo-corrected, time-matched mean change from baseline QTcI at the 95% upper confidence interval (UCI; one-sided). The pre-specified clinically significant change for betrixaban-treated groups was > 10 ms (95% UCI, one-sided). Subjects were monitored for safety and tolerability.

Results: Mean QTcI change was < 10 ms for both betrixaban groups at all time points; expected changes were observed for moxifloxacin, establishing assay sensitivity. Correlation between betrixaban plasma concentration and QTcI duration confirmed the absence of effect on QT.

Conclusions: Betrixaban at therapeutic and supratherapeutic doses did not cause clinically relevant changes in QTcI intervals or other electrocardiographic parameters. Betrixaban was well tolerated.

Keywords::

• antithrombotic agent
• betrixaban
• coagulation factor Xa
• ICH E14 guidance
• QTcI interval

Acknowledgments

Premier Research Group (Philadelphia, PA, USA) was responsible for data management, statistical analysis and programming. R Kahn, MD of Charles River Clinical Services Northwest, Inc. (Tacoma, WA, USA) served as Principal Investigator at the study site. J Mandema, PhD of Quantitative Solutions (Menlo Park, CA, USA) was responsible for PK analysis. All authors approved the manuscript. Tracey Fine, ELS at Fine Biomedical Communications, Inc. (Chapel Hill, NC, USA) provided professional medical writing and editing services funded by Portola Pharmaceuticals, Inc.