Oral Rivaroxaban in Children With Venous Thrombosis (EINSTEINJunior)

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

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.

Study Overview

• Status: Completed
• Conditions: Venous Thrombosis
• Intervention / Treatment: Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Active comparator; Drug: Rivaroxaban (BAY59-7939) suspension

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • South Brisbane, Australia, 4101
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
  • Victoria
    • Parkville, Victoria, Australia, 3052
• Austria
  • Wien, Austria, 1090
  • Oberösterreich
    • Linz, Oberösterreich, Austria, 4020
  • Steiermark
    • Graz, Steiermark, Austria, 8036
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
• Canada
  • Quebec, Canada, G1V 4G2
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
    • Ottawa, Ontario, Canada, K1H 8L1
    • Toronto, Ontario, Canada, M5G 1X8
• France
  • BORDEAUX cedex, France, 33076
  • Montpellier Cedex, France, 34295
  • NANTES Cedex 1, France, 44093
  • Paris, France, 75015
  • Paris, France, 75019
  • Rennes Cedex, France, 35033
  • TOULOUSE Cedex 9, France, 31059
• Germany
  • Berlin, Germany, 13353
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
  • Bayern
    • Erlangen, Bayern, Germany, 91054
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
  • Schleswig-Holstein
    • Lübeck, Schleswig-Holstein, Germany, 23538
• Israel
  • Beer Sheva, Israel, 8410101
  • Haifa, Israel, 3109601
  • Jerusalem, Israel, 9112001
  • Petach Tikva, Israel, 4920235
  • Ramat Gan, Israel, 5262000
• Italy
  • Liguria
    • Genova, Liguria, Italy, 16147
  • Lombardia
    • Milano, Lombardia, Italy, 20122
    • Pavia, Lombardia, Italy, 27100
  • Piemonte
    • Torino, Piemonte, Italy, 10126
  • Puglia
    • Bari, Puglia, Italy, 70124
  • Veneto
    • Padova, Veneto, Italy, 35128
• Netherlands
  • Amsterdam, Netherlands
  • Amsterdam, Netherlands, 1081 HV
  • Nijmegen, Netherlands, 6525 GA
  • Rotterdam, Netherlands, 3015 GJ
  • Utrecht, Netherlands, 3584 CX
• Switzerland
  • Bern, Switzerland, 3010
  • Luzern, Switzerland, 6000
  • Zürich, Switzerland, 8032
  • Basel-Stadt
    • Basel, Basel-Stadt, Switzerland, 4056
  • Sankt Gallen
    • St. Gallen, Sankt Gallen, Switzerland, 9006
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202-3500
  • California
    • Los Angeles, California, United States, 90027-6089
    • Orange, California, United States, 92868-3974
  • Illinois
    • Chicago, Illinois, United States, 60611
  • Indiana
    • Indianapolis, Indiana, United States, 46202
  • Michigan
    • Detroit, Michigan, United States, 48201-2196
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
  • New York
    • New Hyde Park, New York, United States, 11040
  • Ohio
    • Cleveland, Ohio, United States, 44106-2602
    • Columbus, Ohio, United States, 43205-2696
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
  • Texas
    • Houston, Texas, United States, 77030
  • Virginia
    • Richmond, Virginia, United States, 23298

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18; 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); 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.
Active Comparator: Comparator, Age: 12 - <18 years; 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; 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).
Experimental: Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years; 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); 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.
Experimental: Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years; 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; Subjects aged were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily.
Active Comparator: Comparator, Age: 6 - <12 years; 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; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Janssen Research & Development, LLC

Publications and helpful links

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2013
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: September 11, 2012
• First Submitted That Met QC Criteria: September 11, 2012
• First Posted (Estimate): September 13, 2012

Study Record Updates

• Last Update Posted (Actual): September 21, 2017
• Last Update Submitted That Met QC Criteria: August 25, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: 14373; 2011-004539-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No