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

Primary Purpose

Venous Thromboembolism

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Rivaroxaban (Xarelto, BAY59-7939)
Sponsored by
Bayer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Venous Thromboembolism focused on measuring Pediatric

Eligibility Criteria

6 Months - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Healthcare of Atlanta

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Rivaroxaban

Arm Description

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
November 24, 2014
Last Updated
July 24, 2018
Sponsor
Bayer
Collaborators
Janssen Research & Development, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02309411
Brief Title
EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis
Acronym
EINSTEINJr
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
January 15, 2015 (Actual)
Primary Completion Date
April 5, 2017 (Actual)
Study Completion Date
April 5, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
Collaborators
Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Venous Thromboembolism
Keywords
Pediatric

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
46 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rivaroxaban
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban (Xarelto, BAY59-7939)
Intervention Description
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
Primary Outcome Measure Information:
Title
Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events
Description
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).
Time Frame
During or within 2 days after stop of study treatment (up to 32 days)
Secondary Outcome Measure Information:
Title
Number of Subjects With Symptomatic Recurrent Venous Thromboembolism
Description
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.
Time Frame
From start of the study treatment up to 30-days post study treatment period (approximately 60 days)
Title
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging
Description
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.
Time Frame
At the end of the 30-day treatment period
Title
Change From Baseline in Prothrombin Time at Specified Time Points
Description
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.
Time Frame
Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose); Day 30 (10-16 hours post-dose)
Title
Change From Baseline in Activated Partial Thromboplastin Time at Specified Time Points
Description
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.
Time Frame
Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose); Day 30 (10-16 hours post-dose)
Title
Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points
Description
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.
Time Frame
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)
Other Pre-specified Outcome Measures:
Title
Anti-factor Xa Values at Specified Time Points
Description
The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. The anti-factor Xa assay is designed to measure plasma heparin, low molecular weight heparin and other anticoagulants. In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame
Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose) and Day 30 (10-16 hours post-dose)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
City
Pensacola
State/Province
Florida
ZIP/Postal Code
32504
Country
United States
Facility Name
Children's Healthcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
City
Wien
ZIP/Postal Code
1090
Country
Austria
City
São Paulo
State/Province
Sao Paulo
ZIP/Postal Code
01227-200
Country
Brazil
City
São Paulo
Country
Brazil
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
City
Budapest
ZIP/Postal Code
1097
Country
Hungary
City
Jerusalem
ZIP/Postal Code
9112001
Country
Israel
City
Ramat Gan
ZIP/Postal Code
5262000
Country
Israel
City
Milano
State/Province
Lombardia
ZIP/Postal Code
20122
Country
Italy
City
Torino
State/Province
Piemonte
ZIP/Postal Code
10126
Country
Italy
City
Padova
State/Province
Veneto
ZIP/Postal Code
35128
Country
Italy
City
Setagaya
State/Province
Tokyo
ZIP/Postal Code
157-8535
Country
Japan
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
City
Olsztyn
ZIP/Postal Code
10-561
Country
Poland
City
Moscow
ZIP/Postal Code
117997
Country
Russian Federation
City
Nizhny Novgorod
ZIP/Postal Code
603136
Country
Russian Federation
City
St. Petersburg
ZIP/Postal Code
197022
Country
Russian Federation
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
City
Valencia
ZIP/Postal Code
46026
Country
Spain
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
City
Newcastle Upon Tyne
State/Province
Tyne And Wear
ZIP/Postal Code
NE1 4LP
Country
United Kingdom
City
Birmingham
State/Province
West Midlands
ZIP/Postal Code
B4 6NH
Country
United Kingdom
City
Cardiff
ZIP/Postal Code
CF14 4XW
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
31420317
Citation
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.
Results Reference
derived
Links:
URL
http://www.clinicaltrialsregister.eu/
Description
Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Learn more about this trial

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

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