EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis

Study Overview
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Brief Summary
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The purpose of this study is to find out whether rivaroxaban is safe to use in children and how long it stays in the body. Safety will be assessed by looking at the incidence and types of bleeding events. There will also be a check for worsening of blood clots.

Official Title
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30-day, Single-arm Study of the Safety, Efficacy and the Pharmacokinetic and Pharmacodynamic Properties of Oral Rivaroxaban in Young Children With Various Manifestations of Venous Thrombosis

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: Rivaroxaban (Xarelto, BAY59-7939)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 6 months to < 6 years who have been treated for at least 2 months or, in case of catheter related thrombosis, for at least 6 weeks with LMWH (low molecular weight heparin), fondaparinux and/or VKA (vitamin K antagonist) for documented symptomatic or asymptomatic venous thrombosis - Hemoglobin, platelets, creatinine, alanine aminotransferase (ALT) and bilirubin evaluated within 10 days prior to randomization Informed consent provided Exclusion Criteria: Active bleeding or high risk for bleeding contraindicating anticoagulant therapy Symptomatic progression of venous thrombosis during preceding anticoagulant treatment Planned invasive procedures, including lumbar puncture and removal of non peripherally placed central lines during study treatment An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 Hepatic disease which is associated with either: coagulopathy leading to a clinically relevant bleeding risk, or ALT> 5x upper level of normal (ULN) or total bilirubin > 2x ULN with direct bilirubin > 20% of the total Platelet count < 50 x 10*9/L Hypertension defined as > 95th age percentile Life expectancy < 3 months Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. all human immunodeficiency virus protease inhibitors and the following azole antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically Concomitant use of strong inducers of CYP3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine Hypersensitivity or any other contraindication listed in the local labeling for the comparator treatment or experimental treatment Inability to cooperate with the study procedures Previous randomization to this study Participation in a study with an investigational drug or medical device within 30 days prior to randomization

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>Age and body weight-adjusted twice daily dosing of rivaroxaban to achieve a similar exposure as that observed in adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily | Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* With age and body-weight adjusted twice daily dosing of rivaroxaban as Oral Suspension to achieve a similar exposure as that observed in adults treated with 20 mg rivaroxaban once daily, and no other anticoagulant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events | Major bleeding is defined as overt bleeding and: associated with a fall in hemoglobin of 2 gram/decilitre (g/dL) or more, or leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults, or occurring in a critical site, for example (e.g.) intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding, but associated with: medical intervention, or unscheduled contact (visit or telephone call) with a physician, or cessation (temporary) of study treatment, or discomfort for the child such as pain or impairment of activities of daily life (such as loss of school days or hospitalization). | During or within 2 days after stop of study treatment (up to 32 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Symptomatic Recurrent Venous Thromboembolism | Venous thromboembolism is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. The occurrence of recurrent venous thromboembolism was summarized by age group. Symptomatic recurrence, which is the composite of deep Vein Thrombosis (DVT), non-fatal Pulmonary Embolism (PE), and fatal PE of venous thrombosis, had to be documented using appropriate (repeat) imaging test. | From start of the study treatment up to 30-days post study treatment period (approximately 60 days) | 
| Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging | The occurrence of asymptomatic deterioration in thrombotic burden was summarized by age group. At the end of the 30-day treatment period, a repeat imaging of the thrombus was performed. The images of the index event and repeat imaging were adjudicated by the central independent adjudication committee (CIAC). The thrombotic burden at the time of the index event was compared to the thrombotic burden at the time of repeat imaging. The outcome of the adjudication was classified as normalized, improved, no relevant change, deteriorated, or not evaluable. Due to missing repeated imaging, thrombotic burden assessments were not done in some subjects. | At the end of the 30-day treatment period | 
| Change From Baseline in Prothrombin Time at Specified Time Points | Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. Day 30 (10-16 hours post-dose) was considered as a baseline. | Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose); Day 30 (10-16 hours post-dose) | 
| Change From Baseline in Activated Partial Thromboplastin Time at Specified Time Points | The Activated partial thromboplastin time (aPTT) is a screening test for the intrinsic pathway. Day 30 (10-16 hours post-dose) was considered as a baseline. | Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose); Day 30 (10-16 hours post-dose) | 
| Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points | Concentration of rivaroxaban in plasma was measured at Day 1, 15 and 30 at specified time points. In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. | Day 1 (30-90 minutes, 2.5-4 hours post-dose); Day 15 (2-8 hours post-dose) and Day 30 (10-16 hours post-dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric