EINSTEIN Junior: 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 evaluate comparative efficacy and safety of rivaroxaban to standard of care in children with acute venous thromboembolism.

Official Title
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Multicenter, Open-label, Active-controlled, Randomized Study to Evaluate the Efficacy and Safety of an age-and Body Weight-adjusted Rivaroxaban Regimen Compared to Standard of Care in Children With Acute Venous Thromboembolism

Conditions
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Venous Thromboembolism

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged birth to < 18 years with confirmed venous thromboembolism who receive initial treatment with therapeutic dosages of UFH (unfractionated heparin), LMWH (low molecular weight heparin) or fondaparinux and require anticoagulant therapy for at least 90 days. However, children aged birth to < 2 years with catheter-related thrombosis require anticoagulant therapy for at least 30 days. For children younger than 6 months: Gestational age at birth of at least 37 weeks. Oral feeding/nasogastric/gastric feeding for at least 10 days. Body weight ≥2600 g Exclusion Criteria: Active bleeding or bleeding risk contraindicating anticoagulant therapy An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m*2 (in children younger than 1 year, serum creatinine results above 97.5th percentile excludes participation) 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 109/L Sustained uncontrolled 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), including but not limited to 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, including but not limited to rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine Childbearing potential without proper contraceptive measures, pregnancy or breast feeding

Ages Eligible for Study
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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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY59-7939<br>Rivaroxaban (tablets and oral suspension) Dose: Age and body weight-adjusted dosing of rivaroxaban to achieve a similar exposure as that observed in adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban. | Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily or twice daily, as tablets<br>Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily, twice daily or three times daily, as oral suspension<br>|
| Experimental: Standard of Care<br>Subcutaneous low molecular weight heparin (LMWH), subcutaneous fondaparinux and/or oral vitamin K antagonist (VKA) Dose : as per standard of care | Drug: Standard of Care<br>* LMWH (low molecular weight heparin) or fondaparinux or vitamin K antagonist (VKA) therapy. dose : as per standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period | The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference population | During the main study treatment period (i.e., 3 months, except for children with central venous catheter venous thromboembolism (CVC-VTE) aged <2 years for whom it was 1 month) | 
| Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period | The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference population | During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month) | 
| Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period | Incidence rates for all children except those aged < 2 years with catheter-related thrombosis. If no participant in the specific subgroup entered in the specific optional extension period, no analysis of an outcome was possible., The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference Population. | During extended treatment period: up to month 12. | 
| Number of Subjects With the Composite of All Symptomatic Recurrent Venous Thromboembolism During the 30 Days Post-study Treatment Period (i.e. >2 and ≤ 30 Days After Stop of Study Medication) | The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Age group with primary efficacy outcome was reported. | More than 2 and up to 30 days after stop of study medication | 
| Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period | The Central independent adjudication committee (CIAC) classified bleeding as: Major bleeding defined as overt bleeding and: · associated with a fall in hemoglobin of 2 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, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding 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 (temporary) cessation 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 the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month) | 
| Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period | Incidence rates for all children except those aged < 2 years with catheter-related thrombosis. If no participant entered in the specific optional extension period, no analysis of an outcome was possible. The CIAC classified bleeding as: Major bleeding defined as overt bleeding and: associated with a fall in hemoglobin of 2 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, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding defined as overt bleeding not meeting the criteria for major bleeding, but associated with: medical intervention, or unscheduled contact with a physician, or (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life. | During extended treatment period: up to month 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rates of the Composite of All Symptomatic Recurrent Venous Thromboembolism and Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging During the Main Treatment Period | The secondary efficacy outcome defined as the composite of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration on repeat imaging as assessed by central independent adjudication committee. (CIAC) Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference population | During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month) | 
| AUC(0-24)ss in Plasma | AUC(0-24)ss: Area under the concentration vs. time curve from time 0 to 24 hours at steady state. | over 24 hours | 
| Cmax,ss in Plasma | Maximum drug concentration in measured matrix at steady state during a dosage interval | 0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours (one dosing interval in steady state) | 
| Ctrough,ss in Plasma | Ctrough,ss refers to the drug concentration at the end of the dosage interval at steady state | 0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours(one sampling interval in steady state) | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. | Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. | Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. | Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. 'NA' denotes the data that cannot be calculated. | Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. 'NA' denotes the data that cannot be calculated. | Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. | Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. | Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60 | 
| Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years | Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. | Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. | Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. | Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. | Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. 'NA' denotes the data that cannot be calculated. | Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. 'NA' denotes the data that cannot be calculated. | Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. | Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. | Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 | 
| Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years | The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V,VIII, IX, X, XI and XII. The initial read-out is in seconds. | Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 | 
| Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. | Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 24 hours on Day 90 | 
| Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. | Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 24 hours on Day 90 | 
| Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. | Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 16 hours on Day 90 | 
| Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. | Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 16 hours on Day 90 | 
| Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. 'NA' denotes the data that cannot be calculated. | Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 | 
| Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. 'NA' denotes the data that cannot be calculated. | Up to 3 hours post dose on Day 30, up to 6 hours post dose on Day 60, and up to 16 hours on Day 90 | 
| Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. 'NA' denotes the data that cannot be calculated. | Up to 3 hours post dose on Day 30, up to 6 hours post dose on Day 60, up to 16 hours on Day 90 and follow-up up to 30 days | 
| Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years | This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. | Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 | 

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