Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study |
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| Authors: | Anthonie W. A. Lensing Christoph Male Guy Young Dagmar Kubitza Gili Kenet M. Patricia Massicotte Anthony Chan Angelo C. Molinari Ulrike Nowak-Goettl Ákos F. Pap Ivet Adalbo William T. Smith Amy Mason Kirstin Thelen Scott D. Berkowitz Mark Crowther Stephan Schmidt Victoria Price Martin H. Prins Paul Monagle |
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| Affiliation: | 1.Bayer AG, Research and Development, Thrombosis and Hematology,Wuppertal,Germany;2.Department of Paediatrics,Medical University of Vienna,Wien,Austria;3.Children’s Hospital Los Angeles,Los Angeles,USA;4.Sheba Medical Center,TelHashomer,Israel;5.University of Alberta,Edmonton,Canada;6.Department of Pediatrics,McMaster University,Hamilton,Canada;7.Giannina Gaslini Children’s Hospital,Genoa,Italy;8.University Hospital Schleswig-Holstein,Kiel,Germany;9.Department of Medicine,Hematology and Thromboembolism McMaster University,Hamilton,Canada;10.Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics University of Florida,Orlando,USA;11.Department of Pediatrics, Division of Pediatric Hematology-Oncology Dalhousie University,Halifax,Canada;12.Maastricht University Medical Center (MUMC+),Maastricht,The Netherlands;13.Royal Children’s Hospital, University of Melbourne, Murdoch Childrens Research Institute,Melbourne,Australia |
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| Abstract: | BackgroundVenous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.MethodsEINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.ConclusionsEINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.Trial registrationClinicaltrials.gov NCT02234843, registered on 9 September 2014. |
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