Oral Rivaroxaban in 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. There will also be a check for bleeding and 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 Children With Various Manifestations of Venous Thrombosis

Conditions
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Venous Thrombosis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 6 to < 18 years with documented symptomatic or asymptomatic venous thrombosis treated for at least 2 months or, in case of catheter related thrombosis, treated for at least 6 weeks with LMWH (low molecular weight heparin), , fondaparinux and/or VKA (vitamin K antagonist). Informed consent provided and, if applicable, child assent 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 m2 Hepatic disease which is associated with 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

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18<br>Subjects aged from 12 - <18 years were administered with age and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR (immediate-release) tablet once daily (OD) under fed conditions for 30 days. Subjects with a body weight of 14 to less than 50 kilogram (kg) received a dose (equivalent to 20 milligram [mg] in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of greater than or equal to 50 kg received a dose of 20 mg. | Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* Subjects were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days.<br>|
| Active Comparator: Comparator, Age: 12 - <18 years<br>Subjects aged from 12 - <18 years received comparator as per standard of care. The dosage given was to be adjusted based on the individual body weight (low molecular weight heparin, fondaparinux) or international normalized ratio (INR) adjusted (vitamin K antagonist). | Drug: Active comparator<br>* Subjects received comparator as per standard of care. The dosage given was to be adjusted based on the individual body weight (low molecular weight heparin, fondaparinux) or international normalized ratio (INR) adjusted (vitamin K antagonist).<br>|
| Experimental: Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years<br>Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days. Subjects with a body weight of 14 to less than 50 kg received a dose (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of greater than or equal to 50 kg received a dose of 20 mg. | Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* Subjects were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days.<br>|
| Experimental: Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years<br>Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily (BID). Subjects with a body weight of 9 to less than 50 kg received a total daily dose (equivalent to 20 mg in adults) ranging from 6.4 to 15 mg and subjects with a body weight of greater than or equal to 50 kg received a total daily dose of 20 mg. | Drug: Rivaroxaban (BAY59-7939) suspension<br>* Subjects aged were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily.<br>|
| Active Comparator: Comparator, Age: 6 - <12 years<br>Subjects aged from 6 - <12 years received comparator as per standard of care. The dosage given was to be adjusted based on the individual body weight (low molecular weight heparin, fondaparinux) or INR-adjusted (vitamin K antagonist). | Drug: Active comparator<br>* Subjects received comparator as per standard of care. The dosage given was to be adjusted based on the individual body weight (low molecular weight heparin, fondaparinux) or international normalized ratio (INR) adjusted (vitamin K antagonist).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Major and Clinically Relevant Non-Major Bleeding Events | Central independent adjudication committee (CIAC) classified bleeding as follows: 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, e.g. intracranial, intraspinal, intraocular, pericardial, intra-articular, 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). | From start of study drug administration until end of the 30-day treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Symptomatic Recurrent Venous Thromboembolism | The occurrence of recurrent venous thromboembolism was summarized by age group. Symptomatic recurrence of venous thrombosis was documented by the appropriate imaging test. | From start of study drug administration until end of the 30-day treatment period | 
| Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden | The occurrence of asymptomatic deterioration in thrombotic burden was summarized by age group. Asymptomatic deterioration in thrombotic burden was documented by the appropriate imaging test and the results were classified as normalized, improved, no relevant change, deteriorated, not evaluable or not available. | Repeat imaging 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. | 0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31 | 
| 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. | 0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31 | 
| Anti-factor Xa Values at Specified Time Points | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | 0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31 | 
| Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points | Geometric and percentage geometric coefficient of variation (%CV) were reported. | 0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31 |