TY - JOUR
T1 - Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study
AU - Lensing, Anthonie W.A.
AU - Male, Christoph
AU - Young, Guy
AU - Kubitza, Dagmar
AU - Kenet, Gili
AU - Patricia Massicotte, M.
AU - Chan, Anthony
AU - Molinari, Angelo C.
AU - Nowak-Goettl, Ulrike
AU - Pap, Ákos F.
AU - Adalbo, Ivet
AU - Smith, William T.
AU - Mason, Amy
AU - Thelen, Kirstin
AU - Berkowitz, Scott D.
AU - Crowther, Mark
AU - Schmidt, Stephan
AU - Price, Victoria
AU - Prins, Martin H.
AU - Monagle, Paul
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/21
Y1 - 2018/12/21
N2 - 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.
AB - 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.
KW - Anticoagulation
KW - Bodyweight-adjusted dosing
KW - Pediatric patients
KW - Rivaroxaban
KW - Venous thromboembolism
UR - http://www.scopus.com/inward/record.url?scp=85059150705&partnerID=8YFLogxK
U2 - 10.1186/s12959-018-0188-y
DO - 10.1186/s12959-018-0188-y
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AN - SCOPUS:85059150705
SN - 1477-9560
VL - 16
JO - Thrombosis Journal
JF - Thrombosis Journal
IS - 1
M1 - 34
ER -