Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

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

doi:10.1186/s12959-018-0188-y

Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Thromb J. 2018 Dec 21:16:34. doi: 10.1186/s12959-018-0188-y. eCollection 2018.

Authors

Anthonie W A Lensing¹, Christoph Male², Guy Young³, Dagmar Kubitza¹, Gili Kenet⁴, M Patricia Massicotte⁵, Anthony Chan⁶, Angelo C Molinari⁷, Ulrike Nowak-Goettl⁸, Ákos F Pap¹, Ivet Adalbo¹, William T Smith¹, Amy Mason¹, Kirstin Thelen¹, Scott D Berkowitz¹, Mark Crowther⁹, Stephan Schmidt¹⁰, Victoria Price¹¹, Martin H Prins¹², Paul Monagle¹³

Affiliations

¹ 1Bayer AG, Research and Development, Thrombosis and Hematology, Building 402, room 304, Aprather Weg 18a, 42113 Wuppertal, Germany.
² 2Department of Paediatrics, Medical University of Vienna, Wien, Austria.
³ 3Children's Hospital Los Angeles, Los Angeles, USA.
⁴ 4Sheba Medical Center, TelHashomer, Israel.
⁵ 5University of Alberta, Edmonton, Canada.
⁶ 6Department of Pediatrics, McMaster University, Hamilton, Canada.
⁷ 7Giannina Gaslini Children's Hospital, Genoa, Italy.
⁸ 8University Hospital Schleswig-Holstein, Kiel, Germany.
⁹ 9Department of Medicine, Hematology and Thromboembolism McMaster University, Hamilton, ON Canada.
¹⁰ 10Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics University of Florida, Orlando, FL USA.
¹¹ 11Department of Pediatrics, Division of Pediatric Hematology-Oncology Dalhousie University, Halifax, Canada.
¹² 12Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
¹³ Royal Children's Hospital, University of Melbourne, Murdoch Childrens Research Institute, Melbourne, Australia.

Abstract

Background: Venous 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.

Methods: EINSTEIN-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.

Conclusions: EINSTEIN-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 registration: Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

Keywords: Anticoagulation; Bodyweight-adjusted dosing; Pediatric patients; Rivaroxaban; Venous thromboembolism.

Associated data

ClinicalTrials.gov/NCT02234843