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EINSTEIN Junior: Oral Rivaroxaban in Children With Venous Thrombosis (EINSTEIN Jr)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02234843
Recruitment Status : Completed
First Posted : September 9, 2014
Results First Posted : April 1, 2020
Last Update Posted : April 1, 2020
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE September 5, 2014
First Posted Date  ICMJE September 9, 2014
Results First Submitted Date  ICMJE January 29, 2020
Results First Posted Date  ICMJE April 1, 2020
Last Update Posted Date April 1, 2020
Actual Study Start Date  ICMJE November 13, 2014
Actual Primary Completion Date January 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2020)
  • Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period [ Time Frame: 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) ]
    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
  • Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period [ Time Frame: 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) ]
    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
  • Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period [ Time Frame: During extended treatment period: up to month 12. ]
    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.
  • 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) [ Time Frame: More than 2 and up to 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.
  • Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period [ Time Frame: 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) ]
    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).
  • Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period [ Time Frame: During extended treatment period: up to month 12. ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 5, 2014)
  • Composite number of all symptomatic recurrent venous thromboembolism [ Time Frame: Up to 3 months ]
  • Composite number of overt major and clinically relevant non-major bleeding [ Time Frame: Up to 3 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2020)
  • 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 [ Time Frame: 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) ]
    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
  • AUC(0-24)ss in Plasma [ Time Frame: over 24 hours ]
    AUC(0-24)ss: Area under the concentration vs. time curve from time 0 to 24 hours at steady state.
  • Cmax,ss in Plasma [ Time Frame: 0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours (one dosing interval in steady state) ]
    Maximum drug concentration in measured matrix at steady state during a dosage interval
  • Ctrough,ss in Plasma [ Time Frame: 0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours(one sampling interval in steady state) ]
    Ctrough,ss refers to the drug concentration at the end of the dosage interval at steady state
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years [ Time Frame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years [ Time Frame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years [ Time Frame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years [ Time Frame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years [ Time Frame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years [ Time Frame: Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years [ Time Frame: Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60 ]
    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.
  • Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years [ Time Frame: Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years [ Time Frame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years [ Time Frame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years [ Time Frame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years [ Time Frame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years [ Time Frame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years [ Time Frame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years [ Time Frame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 ]
    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.
  • Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years [ Time Frame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 ]
    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.
  • Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years [ Time Frame: 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 ]
    This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.
  • Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years [ Time Frame: 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 ]
    This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.
  • Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years [ Time Frame: 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 ]
    This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.
  • Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years [ Time Frame: 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 ]
    This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.
  • Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years [ Time Frame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60 ]
    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.
  • Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years [ Time Frame: 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 ]
    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.
  • Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years [ Time Frame: 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 ]
    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.
  • Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years [ Time Frame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60 ]
    This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 5, 2014)
Composite number of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration on repeat imaging. [ Time Frame: Up to 3 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE EINSTEIN Junior: Oral Rivaroxaban in Children With Venous Thrombosis
Official Title  ICMJE 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
Brief Summary The purpose of this study is to evaluate comparative efficacy and safety of rivaroxaban to standard of care in children with acute venous thromboembolism.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Venous Thromboembolism
Intervention  ICMJE
  • Drug: Rivaroxaban (Xarelto, BAY59-7939)
    Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily or twice daily, as tablets
  • Drug: Rivaroxaban (Xarelto, BAY59-7939)
    Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily, twice daily or three times daily, as oral suspension
  • Drug: Standard of Care

    LMWH (low molecular weight heparin) or fondaparinux or vitamin K antagonist (VKA) therapy.

    dose : as per standard of care

Study Arms  ICMJE
  • Experimental: BAY59-7939
    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.
    Interventions:
    • Drug: Rivaroxaban (Xarelto, BAY59-7939)
    • Drug: Rivaroxaban (Xarelto, BAY59-7939)
  • Experimental: Standard of Care
    Subcutaneous low molecular weight heparin (LMWH), subcutaneous fondaparinux and/or oral vitamin K antagonist (VKA) Dose : as per standard of care
    Intervention: Drug: Standard of Care
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 13, 2020)
500
Original Estimated Enrollment  ICMJE
 (submitted: September 5, 2014)
160
Actual Study Completion Date  ICMJE January 30, 2019
Actual Primary Completion Date January 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   China,   Finland,   France,   Germany,   Hong Kong,   Hungary,   Ireland,   Israel,   Italy,   Japan,   Mexico,   Netherlands,   Portugal,   Russian Federation,   Singapore,   Slovakia,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries Bulgaria,   Poland,   Romania
 
Administrative Information
NCT Number  ICMJE NCT02234843
Other Study ID Numbers  ICMJE 14372
2014-000565-47 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Janssen Research & Development, LLC
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP