Table 1.
Inclusion and exclusion criteria of the EINSTEIN Jr. study in children younger than 2 years as evaluated in this feasibility assessment
| 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 [15–21]. |
| 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 [15–21]. 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 |
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