EINSTEIN Junior: Oral Rivaroxaban in Children With Venous Thrombosis

NCT02234843 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 143722014-000565-47
• Study Type: interventional
• Target: 500
• Locations: 27 countries
• Sites: 107

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.

Conditions

Venous Thromboembolism

Keywords

Pediatric

Outcome Measures

Primary Outcomes (6)

• Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period

  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

  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)

• Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period

  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

  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)

• Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period

  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.

  During extended treatment period: up to month 12.

• 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)

  The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Age group with primary efficacy outcome was reported.

  More than 2 and up to 30 days after stop of study medication

• Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period

  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).

  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)

• Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period

  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.

  During extended treatment period: up to month 12.

Secondary Outcomes (28)

• 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

  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)

• AUC(0-24)ss in Plasma

  over 24 hours

• Cmax,ss in Plasma

  0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours (one dosing interval in steady state)

• Ctrough,ss in Plasma

  0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours(one sampling interval in steady state)

• Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years

  Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60

Study Arms (2)

BAY59-7939

EXPERIMENTAL

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.

Drug: Rivaroxaban (Xarelto, BAY59-7939)

Standard of Care

EXPERIMENTAL

Subcutaneous low molecular weight heparin (LMWH), subcutaneous fondaparinux and/or oral vitamin K antagonist (VKA) Dose : as per standard of care

Drug: Standard of Care

Interventions

Rivaroxaban (Xarelto, BAY59-7939) DRUG

Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily or twice daily, as tablets

BAY59-7939

Standard of Care DRUG

LMWH (low molecular weight heparin) or fondaparinux or vitamin K antagonist (VKA) therapy. dose : as per standard of care

Standard of Care

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bayer: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (109)

Unknown Facility

Phoenix, Arizona, 85016, United States

Location

Unknown Facility

Little Rock, Arkansas, 72202-3500, United States

Location

Unknown Facility

Los Angeles, California, 90027-6089, United States

Location

Unknown Facility

Los Angeles, California, 90095, United States

Location

Unknown Facility

San Diego, California, 92123, United States

Location

Unknown Facility

Gainesville, Florida, 32610, United States

Location

Unknown Facility

Jacksonville, Florida, 32207, United States

Location

Unknown Facility

Miami, Florida, 33155, United States

Location

Unknown Facility

Pensacola, Florida, 32504, United States

Location

Unknown Facility

St. Petersburg, Florida, 33701, United States

Location

Unknown Facility

Atlanta, Georgia, 30322, United States

Location

Unknown Facility

Chicago, Illinois, 60611, United States

Location

Unknown Facility

Indianapolis, Indiana, 46202, United States

Location

Unknown Facility

Lansing, Michigan, 48912, United States

Location

Unknown Facility

Kansas City, Missouri, 64108-9898, United States

Location

Unknown Facility

Durham, North Carolina, 27710, United States

Location

Unknown Facility

Cincinnati, Ohio, 45229-3039, United States

Location

Unknown Facility

Cleveland, Ohio, 44106-2602, United States

Location

Unknown Facility

Columbus, Ohio, 43205-2696, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, 19104, United States

Location

Unknown Facility

Dallas, Texas, 75235, United States

Location

Unknown Facility

Fort Worth, Texas, 76104, United States

Location

Unknown Facility

Houston, Texas, 77030, United States

Location

Unknown Facility

San Miguel de Tucumán, Tucumán Province, 4000, Argentina

Location

Unknown Facility

Parkville, Victoria, 3052, Australia

Location

Unknown Facility

South Brisbane, 4101, Australia

Location

Unknown Facility

Graz, Styria, 8036, Austria

Location

Unknown Facility

Innsbruck, Tyrol, 6020, Austria

Location

Unknown Facility

Linz, Upper Austria, 4020, Austria

Location

Unknown Facility

Vienna, 1090, Austria

Location

Unknown Facility

Bruxelles - Brussel, 1200, Belgium

Location

Unknown Facility

Edegem, 2650, Belgium

Location

Unknown Facility

Leuven, 3000, Belgium

Location

Unknown Facility

Campinas, São Paulo, 13083-970, Brazil

Location

Unknown Facility

São Paulo, São Paulo, 01227-200, Brazil

Location

Unknown Facility

São Paulo, 04023-061, Brazil

Location

Unknown Facility

São Paulo, 05403-000, Brazil

Location

Unknown Facility

Calgary, Alberta, T3B 6A8, Canada

Location

Unknown Facility

Edmonton, Alberta, T6G 2B7, Canada

Location

Unknown Facility

Hamilton, Ontario, L8N 3Z5, Canada

Location

Unknown Facility

Ottawa, Ontario, K1H 8L1, Canada

Location

Unknown Facility

Toronto, Ontario, M5G 1X8, Canada

Location

Unknown Facility

Montreal, Quebec, H4A 3J1, Canada

Location

Unknown Facility

Hangzhou, Zhejiang, China

Location

Unknown Facility

Beijing, 100034, China

Location

Unknown Facility

Beijing, 100045, China

Location

Unknown Facility

Shanghai, China

Location

Unknown Facility

Turku, 20520, Finland

Location

Unknown Facility

Montpellier, 34059, France

Location

Unknown Facility

Paris, 75015, France

Location

Unknown Facility

Toulouse, 31059, France

Location

Unknown Facility

Erlangen, Bavaria, 91054, Germany

Location

Unknown Facility

Dresden, Saxony, 01307, Germany

Location

Unknown Facility

Halle, Saxony-Anhalt, 06120, Germany

Location

Unknown Facility

Berlin, 13353, Germany

Location

Unknown Facility

Hong Kong, Hong Kong

Location

Unknown Facility

Budapest, 1097, Hungary

Location

Unknown Facility

Crumlin, Dublin, 12, Ireland

Location

Unknown Facility

Afula, 1834111, Israel

Location

Unknown Facility

Jerusalem, 9112001, Israel

Location

Unknown Facility

Petah Tikva, 4920235, Israel

Location

Unknown Facility

Ramat Gan, 5262000, Israel

Location

Unknown Facility

Milan, Lombardy, 20122, Italy

Location

Unknown Facility

Turin, Piedmont, 10126, Italy

Location

Unknown Facility

Padua, Veneto, 35128, Italy

Location

Unknown Facility

Ōbu, Aichi-ken, 474-8710, Japan

Location

Unknown Facility

Azumino, Nagano, 399-8288, Japan

Location

Unknown Facility

Bunkyo-ku, Tokyo, 113-8655, Japan

Location

Unknown Facility

Guadalajara, Jalisco, Mexico

Location

Unknown Facility

Mexico City, Mexico City, 06720, Mexico

Location

Unknown Facility

Amsterdam, 1105 AZ, Netherlands

Location

Unknown Facility

Groningen, 9713 GZ, Netherlands

Location

Unknown Facility

Nijmegen, 6525 GA, Netherlands

Location

Unknown Facility

Rotterdam, 3015 CE, Netherlands

Location

Unknown Facility

Utrecht, 3584 CX, Netherlands

Location

Unknown Facility

Carnaxide, Lisbon District, 2795-53, Portugal

Location

Unknown Facility

Kazan', 420138, Russia

Location

Unknown Facility

Kemerovo, 650002, Russia

Location

Unknown Facility

Krasnodar, 350013, Russia

Location

Unknown Facility

Moscow, 117997, Russia

Location

Unknown Facility

Moscow, 119049, Russia

Location

Unknown Facility

Nizhny Novgorod, 603136, Russia

Location

Unknown Facility

Saint Petersburg, 197022, Russia

Location

Unknown Facility

Saint Petersburg, 197110, Russia

Location

Unknown Facility

Volgograd, 400138, Russia

Location

Unknown Facility

Yekaterinburg, 620028, Russia

Location

Unknown Facility

Singapore, 119228, Singapore

Location

Unknown Facility

Singapore, 229 899, Singapore

Location

Unknown Facility

Bratislava, 833 41, Slovakia

Location

Unknown Facility

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

Unknown Facility

A Coruña, 15006, Spain

Location

Unknown Facility

Barcelona, 08035, Spain

Location

Unknown Facility

Solna, 171 64, Sweden

Location

Unknown Facility

Bern, 3010, Switzerland

Location

Unknown Facility

Lucerne, 6000, Switzerland

Location

Unknown Facility

Zurich, 8032, Switzerland

Location

Unknown Facility

Adana, 01130, Turkey (Türkiye)

Location

Unknown Facility

Istanbul, 34093, Turkey (Türkiye)

Location

Unknown Facility

Konya, 42080, Turkey (Türkiye)

Location

Unknown Facility

Newcastle upon Tyne, Tyne and Wear, NE1 4LP, United Kingdom

Location

Unknown Facility

Birmingham, West Midlands, B4 6NH, United Kingdom

Location

Unknown Facility

Leeds, West Yorkshire, LS1 3EX, United Kingdom

Location

Unknown Facility

Cardiff, CF14 4XW, United Kingdom

Location

Unknown Facility

Edinburgh, EH9 1LF, United Kingdom

Location

Unknown Facility

Glasgow, G51 4TF, United Kingdom

Location

Unknown Facility

London, SW3 6NP, United Kingdom

Location

Unknown Facility

Manchester, M13 9WL, United Kingdom

Location

Unknown Facility

Oxford, OX3 9DU, United Kingdom

Location

Unknown Facility

Sheffield, S10 2TH, United Kingdom

Location

Related Publications (6)

• 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.

  PMID: 36006613 DERIVED

• 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.

  PMID: 33351120 DERIVED

• 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.

  PMID: 33002131 DERIVED

• 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.

  PMID: 31699660 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.

  PMID: 31420317 DERIVED

• 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.

  PMID: 30598642 DERIVED

MeSH Terms

Conditions

Venous Thromboembolism

Interventions

Rivaroxaban; Standard of Care

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Therapeutic Area Head

clinical-trials-contact@bayer.com

(+) 1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 5, 2014
• First Posted: September 9, 2014
• Study Start: November 13, 2014
• Primary Completion: January 30, 2019
• Study Completion: January 30, 2019
• Last Updated: April 1, 2020
• Results First Posted: April 1, 2020

Record last verified: 2020-03

Locations

SE (1); JP (3); AR (1); HU (1); AU (4); HK (1); NL (5); SL (1); BE (3); ES (3); RU (10); CH (3); TU (3); GB (10); IL (4); DE (4); CA (6); FI (1); CN (4); US (23); IT (3); FR (3); PT (1); IE (1); BR (4); ME (2); SG (2)