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

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.

Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein‐Jr phase 3 dose‐exposure‐response evaluation

“…EINSTEIN-Jr. (clinicaltrials.gov: NCT02234843) is a randomized, open-label, multicenter trial that compared the efficacy and safety of rivaroxaban with those of standard anticoagulants for treatment of VTE and evaluated the PK of rivaroxaban. 15 Clinical efficacy and safety results have previously been published. 6 The study was conducted at 107 sites in Australia, Europe, Israel, Japan, China, South America, and North America.…”

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT)

“…The study protocol, the clinical efficacy and safety results, and the rivaroxaban dose-exposure response have been published. 19,20,25 The statistical analysis plan for this prespecified substudy can be found in the supplemental Data. The institutional review board at each participating center approved the study protocol.…”

“…19 The absolute incidences of study outcomes and relative treatment effects observed with rivaroxaban were similar to those in the large rivaroxaban VTE studies in adults. 19,[23][24][25] We present a predefined subgroup analysis of the safety and efficacy of rivaroxaban and standard anticoagulants in the 114 children who presented with CVT in the EINSTEIN-Jr phase 3 trial. 19…”

Venous Thromboembolism in Children: From Diagnosis to Management

“…Presently, several direct oral anticoagulants (DOACs) are undergoing evaluation in paediatric development programs [ 68 , 69 , 70 , 71 , 72 , 73 ]. Randomized clinical trials for DOACs in paediatric VTE are ongoing.…”