Clinical trial NCT02234843: EINSTEIN Junior: Oral Rivaroxaban in Children With Venous Thrombosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Venous Thromboembolism
Keywords: Pediatric
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2014-09-09
Enrollment: 500
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period
timeFrame: 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)
measure: Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period
timeFrame: 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)
measure: Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period
timeFrame: During extended treatment period: up to month 12.
measure: 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)
timeFrame: More than 2 and up to 30 days after stop of study medication
measure: Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period
timeFrame: 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)
measure: Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period
timeFrame: During extended treatment period: up to month 12.
Secondary outcomes:
measure: 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
timeFrame: 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)
measure: AUC(0-24)ss in Plasma
timeFrame: over 24 hours
measure: Cmax,ss in Plasma
timeFrame: 0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours (one dosing interval in steady state)
measure: Ctrough,ss in Plasma
timeFrame: 0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours(one sampling interval in steady state)
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years
timeFrame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years
timeFrame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years
timeFrame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years
timeFrame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years
timeFrame: Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years
timeFrame: Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years
timeFrame: Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60
measure: Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years
timeFrame: Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years
timeFrame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years
timeFrame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years
timeFrame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years
timeFrame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years
timeFrame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years
timeFrame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years
timeFrame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60
measure: Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years
timeFrame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60
measure: Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years
timeFrame: 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
measure: Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years
timeFrame: 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
measure: Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years
timeFrame: 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
measure: Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years
timeFrame: 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
measure: Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years
timeFrame: Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60
measure: Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years
timeFrame: 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
measure: Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years
timeFrame: 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
measure: Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years
timeFrame: Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Little Rock
country: United States
state: Arkansas
city: Los Angeles
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: San Diego
country: United States
state: California
city: Gainesville
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Pensacola
country: United States
state: Florida
city: Saint Petersburg
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Lansing
country: United States
state: Michigan
city: Kansas City
country: United States
state: Missouri
city: Durham
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Dallas
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Miguel de Tucumán
country: Argentina
state: Tucuman
city: Parkville
country: Australia
state: Victoria
city: South Brisbane
country: Australia
city: Linz
country: Austria
state: Oberösterreich
city: Graz
country: Austria
state: Steiermark
city: Innsbruck
country: Austria
state: Tirol
city: Wien
country: Austria
city: Bruxelles - Brussel
country: Belgium
city: Edegem
country: Belgium
city: Leuven
country: Belgium
city: Campinas
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Sao Paulo
country: Brazil
city: Sao Paulo
country: Brazil
city: Calgary
country: Canada
state: Alberta
city: Edmonton
country: Canada
state: Alberta
city: Hamilton
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Hangzhou
country: China
state: Zhejiang
city: Beijing
country: China
city: Beijing
country: China
city: Shanghai
country: China
city: Turku
country: Finland
city: Montpellier
country: France
city: Paris
country: France
city: TOULOUSE Cedex 9
country: France
city: Erlangen
country: Germany
state: Bayern
city: Halle
country: Germany
state: Sachsen-Anhalt
city: Dresden
country: Germany
state: Sachsen
city: Berlin
country: Germany
city: Hong Kong
country: Hong Kong
city: Budapest
country: Hungary
city: Crumlin
country: Ireland
state: Dublin
city: Afula
country: Israel
city: Jerusalem
country: Israel
city: Petach Tikva
country: Israel
city: Ramat Gan
country: Israel
city: Milano
country: Italy
state: Lombardia
city: Torino
country: Italy
state: Piemonte
city: Padova
country: Italy
state: Veneto
city: Obu
country: Japan
state: Aichi
city: Azumino
country: Japan
state: Nagano
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Ciudad de México
country: Mexico
state: Distrito Federal
city: Guadalajara
country: Mexico
state: Jalisco
city: Amsterdam
country: Netherlands
city: Groningen
country: Netherlands
city: Nijmegen
country: Netherlands
city: Rotterdam
country: Netherlands
city: Utrecht
country: Netherlands
city: Carnaxide
country: Portugal
state: Lisboa
city: Kazan
country: Russian Federation
city: Kemerovo
country: Russian Federation
city: Krasnodar
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Sankt-Peterburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Yekaterinburg
country: Russian Federation
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Bratislava
country: Slovakia
city: Esplugues de LLobregat
country: Spain
state: Barcelona
city: A Coruña
country: Spain
city: Barcelona
country: Spain
city: Solna
country: Sweden
city: Bern
country: Switzerland
city: Luzern
country: Switzerland
city: Zürich
country: Switzerland
city: Adana
country: Turkey
city: Istanbul
country: Turkey
city: Konya
country: Turkey
city: Newcastle Upon Tyne
country: United Kingdom
state: Tyne And Wear
city: Birmingham
country: United Kingdom
state: West Midlands
city: Leeds
country: United Kingdom
state: West Yorkshire
city: Cardiff
country: United Kingdom
city: Edinburgh
country: United Kingdom
city: Glasgow
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Oxford
country: United Kingdom
city: Sheffield
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Palumbo JS, Lensing AWA, Brandao LR, Hooimeijer HL, Kenet G, van Ommen H, Pap AF, Majumder M, Kubitza D, Thelen K, Willmann S, Prins MH, Monagle P, Male C. Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr. Blood Adv. 2022 Nov 22;6(22):5821-5828. doi: 10.1182/bloodadvances.2022008160.
citation: Connor P, Sanchez van Kammen M, Lensing AWA, Chalmers E, Kallay K, Hege K, Simioni P, Biss T, Bajolle F, Bonnet D, Grunt S, Kumar R, Lvova O, Bhat R, Van Damme A, Palumbo J, Santamaria A, Saracco P, Payne J, Baird S, Godder K, Labarque V, Male C, Martinelli I, Morales Soto M, Motwani J, Shah S, Hooimeijer HL, Prins MH, Kubitza D, Smith WT, Berkowitz SD, Pap AF, Majumder M, Monagle P, Coutinho JM. Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT). Blood Adv. 2020 Dec 22;4(24):6250-6258. doi: 10.1182/bloodadvances.2020003244.
citation: Thom K, Lensing AWA, Nurmeev I, Bajolle F, Bonnet D, Kenet G, Massicotte MP, Karakas Z, Palumbo JS, Saracco P, Amedro P, Chain J, Chan AK, Ikeyama T, Lam JCM, Gauger C, Pap AF, Majumder M, Kubitza D, Smith WT, Berkowitz SD, Prins MH, Monagle P, Young G, Male C. Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE). Blood Adv. 2020 Oct 13;4(19):4632-4639. doi: 10.1182/bloodadvances.2020002637.
citation: Male C, Lensing AWA, Palumbo JS, Kumar R, Nurmeev I, Hege K, Bonnet D, Connor P, Hooimeijer HL, Torres M, Chan AKC, Kenet G, Holzhauer S, Santamaria A, Amedro P, Chalmers E, Simioni P, Bhat RV, Yee DL, Lvova O, Beyer-Westendorf J, Biss TT, Martinelli I, Saracco P, Peters M, Kallay K, Gauger CA, Massicotte MP, Young G, Pap AF, Majumder M, Smith WT, Heubach JF, Berkowitz SD, Thelen K, Kubitza D, Crowther M, Prins MH, Monagle P; EINSTEIN-Jr Phase 3 Investigators. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e18-e27. doi: 10.1016/S2352-3026(19)30219-4. Epub 2019 Nov 5.
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.
citation: Lensing AWA, Male C, Young G, Kubitza D, Kenet G, Patricia Massicotte M, Chan A, Molinari AC, Nowak-Goettl U, Pap AF, Adalbo I, Smith WT, Mason A, Thelen K, Berkowitz SD, Crowther M, Schmidt S, Price V, Prins MH, Monagle P. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. Thromb J. 2018 Dec 21;16:34. doi: 10.1186/s12959-018-0188-y. eCollection 2018.