In the EINSTEIN-Jr clinical trial The largest pediatric DOAC trial conducted for the treatment of VTE and the first to evaluate a liquid formulation in this population1-6
A randomized, multicenter, active-controlled, open-label, phase 3 trial to evaluate XARELTO® vs comparator* for treatment of acute VTE in a pediatric population3,7
Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3
aBodyweight-adjusted rivaroxaban dose equivalent to 20 mg once daily adult dose.
bChildren aged <2 years with CVC-VTE: extension with maximum 2 blocks of 1 month, maximum duration of 3 months; decision to stop or continue treatment made after each 3- or 1-month block.
*Comparator treatment = UFH, LMWH, fondaparinux, or VKA.
CVC-VTE = central venous catheter-related VTE; DOAC = direct oral anticoagulant; FPFV = first patient first visit; LMWH = low-molecular-weight heparin; LPLV = last patient last visit; UFH = unfractionated heparin; VKA = vitamin K antagonist.
EINSTEIN-Jr clinical trial study design3,7
Children aged 0 to 17 years of age with acute VTE initially started on UFH, LMWH, or fondaparinux for ≥5 days before randomization
Randomized in a 2:1 ratio to XARELTO® (n=335) or comparator (n=165), stratified by age and VTE site
- XARELTO® administered as tablets or oral suspension and weight adjusted to achieve drug exposure comparable to 20 mg/day in adults
- Standard anticoagulation*: continued heparin treatment or switched to a vitamin K antagonist
Main treatment duration: 3 months, or 1 month in children <2 years with catheter-related VTE
- With the option to continue treatment in 3-month increments up to a maximum of 12 months, with the exception of children <2 years of age with CVC-VTE who were treated with XARELTO® in 1-month increments up to a maximum of 3 months
- Primary efficacy outcome: symptomatic recurrent VTE in ITT population
Secondary efficacy outcomes:
- Composite of recurrent VTE and deterioration on repeated vascular (clot) imaging
- Principal safety outcome: composite of overt major bleeding and clinically relevant nonmajor bleeding†
Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3‡
*Comparators were given at therapeutic doses, according to international guidelines, and included UFH, LMWH, or fondaparinux. Following completion of 5 to 9 days of standard anticoagulation, participants continued with heparin treatment or were switched to a VKA at the discretion of the treating physician for a main study treatment period of 3 months (or 1 month for children <2 years with CVC-VTE). A diagnostic imaging test was obtained at baseline and at the end of the main study treatment. When clinically necessary, treatment was extended up to 12 months in total (or up to 3 months in total for children <2 years with CVC-VTE.)1,3,7
†Clinically relevant nonmajor bleeding is clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. Major bleeding is clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
‡The study could not be powered to independently show noninferiority for efficacy of rivaroxaban in comparison to standard therapy in children; therefore, interpretation of the results relies in part on extrapolation of data obtained with rivaroxaban in adults; hence, there was no formal a priori sample size calculation.
CVC-VTE = central venous catheter-related VTE; ITT = intent-to-treat; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VKA = vitamin K antagonist.