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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-002385-74 | EudraCT Number |
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| Name | Class |
|---|---|
| Janssen Research & Development, LLC | INDUSTRY |
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The purpose of this study is to find out whether rivaroxaban is safe and effective to use in children age newborn to less than 6 months and how long it stays in the body and how it is used 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.
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion criteria, who have been treated for at least five days with heparin and /or vitamin K antagonist (VKA) for confirmed symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study treatment consists of a 7-day treatment with an age- and body weight-adjusted three times daily, approximately 8 hours apart oral rivaroxaban dosing to achieve a similar exposure as that observed in adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be provided as granules for preparation of an oral suspension (1 mg/mL after re-suspension) using a t.i.d. regimen with 8-hour intervals. An ultrasound will be performed before starting rivaroxaban at treatment day 1 and after the end of rivaroxaban treatment at day 8. The last dose of rivaroxaban treatment will be followed by a 30-day post study treatment period, regardless of the duration of study drug administration. After cessation of rivaroxaban, it is at the investigator's discretion to continue with anticoagulants. The principal safety outcome is the combination of major and clinically relevant non-major bleeding. The efficacy outcome is the composite of all symptomatic recurrent thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging. All suspected recurrent thromboembolism, asymptomatic deterioration in thrombotic burden on repeat imaging, deaths, as well as all episodes of bleeding will be evaluated by a central independent adjudication committee (CIAC). Adjudication results will be the basis for the final analyses.
For all children, visits are scheduled at regular time points (see Table 1). Enrolled children who are not treated or those with premature discontinuation of rivaroxaban will at least be seen at the end of the study treatment period. During all contacts, the treatment and clinical course of the child will be evaluated. Children with suspected efficacy or safety outcomes will undergo confirmatory testing as per standard of care. Blood samples for pharmacokinetic (PK)/pharmacodynamics (PD) will be taken at defined time points (see Table 2).
An Independent Data Monitoring Committee (DMC) will monitor the children's safety during the study and give recommendations to the steering committee.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Experimental | Rivaroxaban oral suspension from granules will be dosed according to body weight as oral 0.1% suspension (1 mg/mL) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Drug | Body weight adjusted dosing of rivaroxaban to achieve a similar exposure in the range as that observed in adults treated for venous thromboembolism (VTE) with 20 mg once daily. |
| Measure | Description | Time Frame |
|---|---|---|
| Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 1 | Concentration of pharmacokinetic parameters of rivaroxaban in plasma was evaluated. | 30 minutes to 1.5 hours post-dose; 2 to 4 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 1 (tid dosing) |
| Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 3 | Concentration of pharmacokinetic parameters of rivaroxaban in plasma was evaluated. | 2 to 8 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 3 (tid dosing) |
| Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 8 | Concentration of pharmacokinetic parameters of rivaroxaban in plasma was evaluated. | 10 to 16 hours post-dose on Day 8 (bid dosing) |
| Change From Baseline in Prothrombin Time at Day 1 | Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. | 10-16 hours post-dose on Day 8 (baseline), 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing) |
| Change From Baseline in Prothrombin Time at Day 3 | Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. | 10-16 hours post-dose on Day 8 (baseline), 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing) |
| Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at Day 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants 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/deciliter (g/dL) or more, •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, example: 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bayer Study Director | Bayer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vienna | 1090 | Austria | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31420317 | Derived | Monagle P, Lensing AWA, Thelen K, Martinelli I, Male C, Santamaria A, Samochatova E, Kumar R, Holzhauer S, Saracco P, Simioni P, Robertson J, Grangl G, Halton J, Connor P, Young G, Molinari AC, Nowak-Gottl U, Kenet G, Kapsa S, Willmann S, Pap AF, Becka M, Twomey T, Beyer-Westendorf J, Prins MH, Kubitza D; EINSTEIN-Jr Phase 2 Investigators. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol. 2019 Oct;6(10):e500-e509. doi: 10.1016/S2352-3026(19)30161-9. Epub 2019 Aug 13. |
| Label | URL |
|---|---|
| Click here to find information about studies related to Bayer Healthcare products conducted in Europe. | View source |
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Overall, 11 participants were screened, of these 1 participant was not included in the study due to withdrawal by parent. A total of 10 participants were assigned to treatment.
Study was conducted at 9 study centers in 7 countries between 19 November 2015 (first participant first visit) and 18 December 2017 (last participant last visit).
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| ID | Title | Description |
|---|---|---|
| FG000 | Rivaroxaban (BAY59-7939) Suspension Bid | Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 3.2 milligram (mg) oral dose of rivaroxaban oral suspension twice daily (bid) for 7 days. |
| FG001 | Rivaroxaban (BAY59-7939) Suspension Tid | Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 2.9 mg oral dose of rivaroxaban oral suspension thrice daily (tid) for 7 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety analysis set (SAF) included all participants who received at least one dose of rivaroxaban.
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| ID | Title | Description |
|---|---|---|
| BG000 | Rivaroxaban (BAY59-7939) Suspension Bid | Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 3.2 milligram (mg) oral dose of rivaroxaban oral suspension twice daily (bid) for 7 days. |
| BG001 | Rivaroxaban (BAY59-7939) Suspension Tid |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | SAF included all participants who received at least one dose of rivaroxaban. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 1 | Concentration of pharmacokinetic parameters of rivaroxaban in plasma was evaluated. | Pharmacokinetic (PK) analysis set (PKS) included all participants with at least one PK sample in accordance with the PK sampling strategy. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | 30 minutes to 1.5 hours post-dose; 2 to 4 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 1 (tid dosing) |
|
From start of study treatment up to 30 days after the last administration of study drug
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rivaroxaban (BAY59-7939) Suspension Bid | Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 3.2 milligram (mg) oral dose of rivaroxaban oral suspension twice daily (bid) for 7 days. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial thrombosis | Cardiac disorders | MedDRA (20.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA (20.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Therapeutic Area Head | Bayer | +1-888-84-22937 | clinical-trials-contact@bayer.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 9, 2016 | Jun 11, 2018 | SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Nov 15, 2016 | Jun 11, 2018 | Prot_001.pdf |
| ID | Term |
|---|---|
| D013923 | Thromboembolism |
| ID | Term |
|---|---|
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000069552 | Rivaroxaban |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D009025 | Morpholines |
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The Activated partial thromboplastin time (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. |
| 10-16 hours post-dose on Day 8 (baseline), 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing) |
| Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at Day 3 | The Activated partial thromboplastin time (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. | 10-16 hours post-dose on Day 8 (baseline), 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing) |
| Anti-factor Xa Activity (Anti-Xa) Values at Day 1 | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing) |
| Anti-factor Xa Activity (Anti-Xa) Values at Day 3 | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing) |
| Anti-factor Xa Activity (Anti-Xa) Values at Day 8 | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | 10-16 hours post-dose on Day 8 (both bid and tid dosing) |
| From start of study drug administration until 30-day post study treatment period |
| Number of Participants With Symptomatic Recurrent Venous Thromboembolism and Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging | Symptomatic recurrence of thromboembolism and asymptomatic deterioration was documented using the appropriate imaging test and confirmed by CIAC which was unaware of treatment assignment. Asymptomatic deterioration in thrombotic burden on repeat imaging, as assessed by the CIAC. Adjudication results were the basis for the final analyses. | From start of study drug administration until 30-day post study treatment period |
| Montpellier |
| 34059 |
| France |
| Erlangen | 91052 | Germany |
| Ramat Gan | 5262000 | Israel |
| Milan | Lombardy | 20122 | Italy |
| Barcelona | 08035 | Spain |
| Madrid | 28007 | Spain |
| Madrid | 28046 | Spain |
| Izmir | 35-100 | Turkey (Türkiye) |
Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 2.9 mg oral dose of rivaroxaban oral suspension thrice daily (tid) for 7 days. |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| Months |
|
| Sex: Female, Male | SAF included all participants who received at least one dose of rivaroxaban. | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | SAF included all participants who received at least one dose of rivaroxaban. | Count of Participants | Participants |
|
| Weight | SAF included all participants who received at least one dose of rivaroxaban. | Mean | Standard Deviation | Kilogram (kg) |
|
| Prothrombin Time | PD analysis set (PDS) included all participants with at least one blood sample for clotting parameters in accordance with the PD sampling strategy. | Mean | Standard Deviation | Seconds (sec) |
|
| Activated Partial Thromboplastin Time (aPTT) | PDS included all participants with at least one blood sample for clotting parameters in accordance with the PD sampling strategy. | Mean | Standard Deviation | Seconds (sec) |
|
| OG001 |
| Rivaroxaban (BAY59-7939) Suspension Tid |
Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 2.9 mg oral dose of rivaroxaban oral suspension thrice daily (tid) for 7 days. |
|
|
| Secondary | Number of Participants 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/deciliter (g/dL) or more, •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, example: 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 | Safety analysis set (SAF) included all participants who received at least one dose of rivaroxaban. | Posted | Number | count of participants | From start of study drug administration until 30-day post study treatment period |
|
|
|
| Secondary | Number of Participants With Symptomatic Recurrent Venous Thromboembolism and Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging | Symptomatic recurrence of thromboembolism and asymptomatic deterioration was documented using the appropriate imaging test and confirmed by CIAC which was unaware of treatment assignment. Asymptomatic deterioration in thrombotic burden on repeat imaging, as assessed by the CIAC. Adjudication results were the basis for the final analyses. | Full analysis set (FAS) included all participants from whom informed consent was obtained and who contributed any data thereafter. | Posted | Number | count of participants | From start of study drug administration until 30-day post study treatment period |
|
|
|
| Primary | Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 3 | Concentration of pharmacokinetic parameters of rivaroxaban in plasma was evaluated. | PKS included all participants with at least one PK sample in accordance with the PK sampling strategy. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | 2 to 8 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 3 (tid dosing) |
|
|
|
| Primary | Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 8 | Concentration of pharmacokinetic parameters of rivaroxaban in plasma was evaluated. | PKS included all participants with at least one PK sample in accordance with the PK sampling strategy. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | 10 to 16 hours post-dose on Day 8 (bid dosing) |
|
|
|
| Primary | Change From Baseline in Prothrombin Time at Day 1 | Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. | Pharmacodynamic (PD) analysis set (PDS) included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | seconds (sec) | 10-16 hours post-dose on Day 8 (baseline), 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing) |
|
|
|
| Primary | Change From Baseline in Prothrombin Time at Day 3 | Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. | PDS included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | seconds (sec) | 10-16 hours post-dose on Day 8 (baseline), 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing) |
|
|
|
| Primary | Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at Day 1 | The Activated partial thromboplastin time (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. | PDS included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | seconds (sec) | 10-16 hours post-dose on Day 8 (baseline), 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing) |
|
|
|
| Primary | Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at Day 3 | The Activated partial thromboplastin time (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. | PDS included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | seconds (sec) | 10-16 hours post-dose on Day 8 (baseline), 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing) |
|
|
|
| Primary | Anti-factor Xa Activity (Anti-Xa) Values at Day 1 | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | PDS included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | microgram per liter (mcg/L) | 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing) |
|
|
|
| Primary | Anti-factor Xa Activity (Anti-Xa) Values at Day 3 | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | PDS included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | microgram per liter (mcg/L) | 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing) |
|
|
|
| Primary | Anti-factor Xa Activity (Anti-Xa) Values at Day 8 | The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. | PDS included all participants with at least 1 blood sample for clotting parameters in accordance with the PD sampling strategy were included in the PD analysis. | Posted | Mean | Standard Deviation | microgram per liter (mcg/L) | 10-16 hours post-dose on Day 8 (both bid and tid dosing) |
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| 0 |
| 5 |
| 0 |
| 5 |
| 1 |
| 5 |
| EG001 | Rivaroxaban (BAY59-7939) Suspension Tid | Participants aged less than 6 months were administered with age- and body weight-adjusted 0.5 to 2.9 mg oral dose of rivaroxaban oral suspension thrice daily (tid) for 7 days. | 0 | 5 | 1 | 5 | 0 | 5 |
Bayer shall own the exclusive rights to all results, data, findings, radiological & diagnostic images, discoveries, inventions & specifications, whether patentable or not, that are originated, conceived, derived, produced, discovered, invented or otherwise made by Center, PI and/or Study Team Physicians and/or Members in connection with the performance of the Study (i.e. Results). Contract Partners hereby assign their rights to the Results to Bayer in advance and Bayer accepts such assignment.
| D010078 |
| Oxazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| 2 to 8 hours post-dose |
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| 7 to 8 hours post-dose |
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