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Table 1 Inclusion and exclusion criteria of the EINSTEIN Jr. study in children younger than 2 years as evaluated in this feasibility assessment

From: Clinical presentation and therapeutic management of venous thrombosis in young children: a retrospective analysis

Eligibility criteria Rationale
Inclusion criteria for children aged < 0.5 year
 Confirmed VTE and initial treatment with therapeutic dosages of UFH, LMWH or fondaparinux and requirement for anticoagulant therapy for at least 3 months (at least 6 weeks for those with catheter-related VTE) Target population
 Gestational age at birth of at least 37 weeks Maturation of organs involved in rivaroxaban absorption and clearance depend on the gestational and postnatal age. Rivaroxaban PK variability is expected to be higher in children born preterm compared to term neonates and older children [15,16,17,18,19,20,21].
 Oral, nasogastric or gastric feeding for at least 10 days Literature data indicates that gastrointestinal conditions are more stable in children with a gestational age of ≥37 weeks who have been on oral feeding for at least 10 days [15,16,17,18,19,20,21]. Rivaroxaban should be taken with food to achieve optimal absorption [22, 23].
 Bodyweight ≥2600 g Above 2600 g representative virtual children could be simulated with the rivaroxaban PBPK model for (term born) neonates
Inclusion criteria for children aged 0.5–2 years
 Confirmed VTE and initial treatment with therapeutic dosages of UFH, LMWH or fondaparinux and requirement for anticoagulant therapy for at least 3 months (at least 6 weeks for those with catheter-related VTE) Target population
Exclusion criteria
 Active bleeding or bleeding risk contraindicating anticoagulant therapy Potential risk factor for (increased) bleeding with any anticoagulant
 Estimated glomerular filtration rate < 30 mL/min/1.73m2 (in children < 1 year, serum creatinine results above 97.5th percentile [24, 25] Potential risk factor for bleeding with any anticoagulant
 Hepatic disease associated with either a coagulopathy leading to a clinically relevant bleeding risk, or ALT > 5× ULN Potential risk factor for bleeding with any anticoagulant
 Platelet count < 50 × 109/L Potential risk factor for bleeding with any anticoagulant
 Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure > 95th age percentile [26] Potential risk factor for bleeding with any anticoagulant
 Life expectancy < 3 months A priori likelihood for the child to not complete the study
 Concomitant use of strong inhibitors of both CYP3A4 and P-gp; Potential for increased rivaroxaban plasma concentrations to a clinically relevant degree
 Concomitant use of strong inducers of CYP3A4 Potential for reduced rivaroxaban plasma concentrations
 Gastrointestinal disease associated with impaired absorption Potential for reduced rivaroxaban plasma concentrations
 Hypersensitivity or any other contraindication listed in the local labeling for rivaroxaban or comparator treatment Contraindication for use of the product
 Participation in a study with an investigational drug or medical device within 30 days prior to randomization Regulatory requirement
  1. VTE denotes venous thromboembolism, UFH unfractionated heparin, LMWH low molecular weight heparin, ALT alanine aminotransferase, ULN upper limit of normal, CYP 3A4 cytochrome P450 isoenzyme 3A4, P-gp P-glycoprotein