Hokusai Study in Pediatric Patients With Confirmed Venous Thromboembolism (VTE)

A Phase 3, Open-label, Randomized, Multi-center, Controlled Trial to Evaluate the Pharmacokinetics and Pharmacodynamics of Edoxaban and to Compare the Efficacy and Safety of Edoxaban With Standard of Care Anticoagulant Therapy in Pediatric Subjects From Birth to Less Than 18 Years of Age With Confirmed Venous Thromboembolism (VTE)

This is an event driven Phase 3, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) parallel group study in subjects with confirmed VTE. This study is designed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of edoxaban and to compare the efficacy and safety of edoxaban against standard of care in pediatric subjects with confirmed VTE.

Study Overview

• Status: Completed
• Conditions: Pulmonary Embolism; Venous Thromboembolism (VTE); Deep Vein Thrombosis (DVT)
• Intervention / Treatment: Drug: Edoxaban; Drug: Standard of Care

Detailed Description

The objective is to demonstrate the non-inferiority of edoxaban to standard of care (SOC; including low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors) in the treatment and secondary prevention of VTE in pediatric subjects with regard to the composite efficacy endpoint (ie, symptomatic recurrent VTE, death as result of VTE, and no change or extension of thrombotic burden) during the first 3-month treatment period.

• Study Type: Interventional
• Enrollment (Actual): 290
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B8001HXM
    • Hospital Italiano Regional del Sur
  • Cordoba, Argentina, X5000JHQ
    • Sanatorio Allende
• Brazil
  • São Paulo, Brazil, 01232-010
    • Hospital Samaritano
  • São Paulo, Brazil, 04013-060
    • Hospital da Luz Amico Saude LTDA
  • São Paulo, Brazil, 04013-060
    • Hospital Infantil Pequeno Príncipe
  • São Paulo, Brazil, 04039-001
    • GRAACC - Grupo de Apoio ao Adolescente e a Crianca com Cancer
  • São Paulo, Brazil, 04039-032
    • UNIFESP - Universidade Federal de São Paulo
  • São Paulo, Brazil, 05403-000
    • Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
  • São Paulo, Brazil, 09030-010
    • HMCG - Hospital e Maternidade Dr. Christovão da Gama
  • Paraná
    • Curitiba, Paraná, Brazil, 81520-060
      • Hospital Erasto Gaertner - Liga Paranaense de Combate Ao Câncer
  • Recife
    • Pernambuco, Recife, Brazil, 50070-550
      • IMIP - Instituto de Medicina Integral Professor Fernando Figueira
  • Rio Grande Do Sul
    • Passo Fundo, Rio Grande Do Sul, Brazil, 99010-080
      • Hospital Sao Vicente de Paulo
    • Passo Fundo, Rio Grande Do Sul, Brazil, 99010-260
      • Hospital da Cidade de Passo Fundo
    • Pôrto Alegre, Rio Grande Do Sul, Brazil, 90620-001
      • Instituto de Cardiologia do Rio Grande do Sul
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-400
      • Hospital de Cancer de Barretos - Fundacao Pio XII
    • Campinas, São Paulo, Brazil, 13083-878
      • Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP
    • Santo André, São Paulo, Brazil, 09190-510
      • Centro Multidisciplinar de Estudos Clinicos - Cemec
    • Votuporanga, São Paulo, Brazil, 15500-003
      • Santa Casa de Votuporanga
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • UMHAT "Sv. Georgi", EAD
  • Sofia, Bulgaria, 1309
    • MHAT - "National Heart Hospital" EAD
  • Sofia, Bulgaria, 1407
    • MHAT 'Tokuda Hospital Sofia', EAD
  • Sofia, Bulgaria, 1612
    • Medical Center for Specialized Ambulatory Medical Assistance for Children's Diseases
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Edmonton Clinic Health Academy
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital
• Chile
  • Maipu, Chile, 9251521
    • Hospital El Carmen Dr. Luis Valentin Ferrada
  • Santiago, Chile, 7591047
    • Clinica Las Condes
• Croatia
  • Rijeka, Croatia, 51000
    • Clinical Hospital Centre Rijeka
  • Zadar, Croatia, 23000
    • General Hospital Zadar
  • Zagreb, Croatia, 10 000
    • Children's Hospital Zagreb
  • Zagreb, Croatia, 10000
    • University Hospital Centre Zagreb, University of Zagreb School of Medicine
• Czechia
  • Brno, Czechia, 613 00
    • Fakultní Nemocnice Brno
  • Hodonin, Czechia, 69501
    • CTC Hodonin s.r.o.
  • Hradec Králové, Czechia, 500 05
    • Dětská klinika Fakultní nemocnice
  • Plzen, Czechia, 305 99
    • University Hospital Pilsen, CZ
• Denmark
  • Aalborg, Denmark, 9000
    • Ålborg Universitetshospital
• El Salvador
  • Salvador
    • San Salvador, Salvador, El Salvador
      • Hospital Nacional de Ninos Benjamin Bloom
• France
  • Angers, France, 49100
    • CHU Angers - Hôpital Hôtel Dieu
  • Clermont-Ferrand, France, 63003
    • CHU Clermont Ferrand - Hôpital d'Estaing
  • Montpellier, France, 34295
    • CHU Arnaud de Villeneuve
  • Finistere
    • Brest, Finistere, France, 29200
      • Clinical Hospital Centre Cavale Blanche BREST
  • Gironde
    • Pessac, Gironde, France, 33600
      • Groupe Hospitalier Sud - Hôpital Haut-Lévêque
  • Haute Garonne
    • Toulouse, Haute Garonne, France, 31059
      • Hôpital des enfants, CHU Toulouse
  • Ille Et Vilaine
    • Rennes, Ille Et Vilaine, France, 35203
      • CHU Rennes - Hôpital sud
• Germany
  • Berlin, Germany, 13353
    • Charite - Campus Virchow-Klinikum
  • Nordrhein Westfalen
    • Essen, Nordrhein Westfalen, Germany, 45122
      • Universitaetsklinikum Essen
• Guatemala
  • Guatemala, Guatemala
    • Unidad de Cirugía Cardiovascular de Guatemala (UNICAR)
  • Guatemala, Guatemala
    • Unidad Nacional de Oncología Pediátrica (UNOP)
• Hungary
  • Budapest, Hungary, 1094
    • Semmelweis University 2nd Department of Pediatrics
  • Budapest, Hungary, H-1097
    • Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont
  • Szeged, Hungary, 6720
    • University of Szeged, Department of Pediatrics
• India
  • Delhi, India, 110076
    • Indraprastha Apollo Hospitals
  • Delhi
    • New Delhi, Delhi, India, 110060
      • Sir Ganga Ram Hospital
  • Gujarat
    • Karamsad, Gujarat, India, 388325
      • Shree Krishna Hospital & Medical Research Centre, H M Patel Centre for Medical Care and Education
    • Surat, Gujarat, India, 395002
      • Nirmal Hospital
  • Karnataka
    • Bangalore, Karnataka, India, 560052
      • Jain Institute of Vascular Sciences
    • Bangalore, Karnataka, India, 560054
      • M. S. Ramaiah Medical College And Hospital
  • Maharashtra
    • Nagpur, Maharashtra, India, 440003
      • Government Medical College and Hospital
  • Punjab
    • Ludhiana, Punjab, India, 141008
      • Christian Medical College
  • West Bengal
    • Kolkata, West Bengal, India, 700017
      • Institute of Child Health
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Jerusalem, Israel, 91120
    • Hadassah Ein Kerem
  • Ramat Gan, Israel, 52621
    • Chaim Sheba Medical Center
• Kenya
  • Nairobi, Kenya, 59857-00200
    • Strathmore University Medical Centre
• Korea, Republic of
  • Seoul, Korea, Republic of, 3080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 3722
    • Severance Hospital, Yonsei University
  • Seoul, Korea, Republic of, 6351
    • Samsung Medical Center
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • American University of Beirut Medical Center
  • Beirut, Lebanon, 166378
    • Saint George University Hospital Medical Center
  • Beirut, Lebanon, 166830
    • Hotel Dieu de France Hospital
• Malaysia
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 15586
      • Hospital Raja Perempuan Zainab II
• Netherlands
  • Rotterdam, Netherlands, 3000 CB
    • Erasmus MC Sophia
• Norway
  • Oslo, Norway, 15-274
    • Oslo University Hospital
• Panama
  • Panamá, Panama, 0843-01103
    • INDICASAT AIP Site 7871
  • Panamá, Panama, 0843-01103
    • INDICASAT AIP Site 7872
• Portugal
  • Braga, Portugal, 4710-243
    • Hospital de Braga
  • Guimarães, Portugal, 4835-044
    • Hospital da Senhora da Oliveira
  • Lisboa, Portugal, 1169-1024
    • Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santa Marta
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria
• Romania
  • Sângeorgiu De Mureş, Romania, 547530
    • S.C Centrul Clinic Mediquest S.R.L
• Russian Federation
  • Kirov, Russian Federation, 610027
    • FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion, FMBA"
  • Moscow, Russian Federation, 117997
    • Russian Scientific Center of Radiology and Nuclear Medicine of Ministry of Health of Russian Federation, Department of Pediatric Oncology
• Serbia
  • Belgrade, Serbia, 11070
    • Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic"
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
• Singapore
  • Singapore, Singapore, 229899
    • KK Women's and Children's Hospital
  • Singapore, Singapore, 119074
    • National University Hospital
• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Centre Ljubljana
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Álava
    • Vitoria, Álava, Spain, 01009
      • Hospital Universitario Araba
• Taiwan
  • Hualien City, Taiwan, 970
    • Buddhist Tzu Chi General Hospital
  • Kaohsiung, Taiwan, 81362
    • Kaohsiung Veterans General Hospital
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taipei City, Taiwan, 11031
    • Taipei Medical University Hospital
• Thailand
  • Bangkok, Thailand, 10300
    • Ramathibodi Hospital
  • Bangkok, Thailand, 10330
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand, 10400
    • Phramongkutklao Hospital
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University Hospital, Faculty of Medicine, Chiang Mai University
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hospital
  • Songkhla, Thailand, 90110
    • Songklanagarind Hospital
• Turkey
  • Adana, Turkey, 1330
    • Cukurova University Faculty of Medicine Balcali Hospital Pediatry Department
  • Ankara, Turkey, 6100
    • Hacettepe University Medical Faculty
  • Ankara, Turkey, 6110
    • Ankara Çocuk Sağlığı Ve Hastalıkları Hematoloji Onkoloji Eğitim Araştırma Hastanesi
  • Istanbul, Turkey, 34093
    • Istanbul University Istanbul Medical Faculty
  • Istanbul, Turkey, 34718
    • Yeditepe University Oncology Hospital
  • Izmir, Turkey, 35040
    • Ege University Medical Faculty
  • Izmir, Turkey, 35170
    • Izmir Tepecik Training and Research Hospital
  • Izmir, Turkey, 35210
    • Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi
  • Kayseri, Turkey, 38039
    • Erciyes University Medical Faculty
  • Mersin, Turkey, 33343
    • Mersin University Health Research and Practice Hospital
• Ukraine
  • Dnipro, Ukraine, 49100
    • Regional Children's Clinical Hospital
  • Kharkiv, Ukraine, 61093
    • CI of Healthcare Regional Children CH Gastroenterology Center Kharkiv NMU
  • Poltava, Ukraine, 36004
    • Children City Clinical Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Banner University Medical Center
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center CAR
    • Stanford, California, United States, 94305-2200
      • Stanford University Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Oak Lawn, Illinois, United States, 60453-2699
      • Advocate Children's Hospital-Oak Lawn
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Helen DeVos Children's Hospital Grand Rapids
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital & Clinics of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • University North Carolina- Chapel Hill
    • Charlotte, North Carolina, United States, 28204
      • Levine Children's Hospital Charlotte
    • Charlotte, North Carolina, United States, 28210
      • The Presbyterian Hospital
    • Greenville, North Carolina, United States, 27858
      • East Carolina University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Hasbro Children's Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Memphis, Tennessee, United States, 38105
      • Le Bonheur Childrens Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-4874
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female pediatric subjects between birth (defined as 38 weeks gestational age) and less than 18 years of age at the time of consent.
2. Pediatric subjects with the presence of documented VTE confirmed by appropriate diagnostic imaging and requiring anticoagulant therapy for at least 90 days.
3. Subjects must have received at least 5 days of heparin therapy prior to randomization to treat the newly identified index VTE. In addition, prior to being randomized to edoxaban or SOC, subjects initially treated with VKA are recommended to have an international normalized ratio (INR) < 2.0.
4. Subject and/or parent(s)/legal guardian(s) or legally acceptable representative is informed and provides signed consent for the child to participate in the study.
5. Female subjects who have menarche must test negative for pregnancy at Screening and must consent to avoid becoming pregnant by using an approved contraception method throughout the study.

Exclusion Criteria:

1. Subjects with active bleeding or high risk of bleeding contraindicating treatment with LMWH, SP Xa inhibitors, VKAs, or direct oral anticoagulants (DOACs; identified high risk of bleeding during prior experimental administration of DOACs).
2. Subjects who have been or are being treated with thrombolytic agents, thrombectomy or insertion of a caval filter for the newly identified index VTE.
3. Administration of antiplatelet therapy is contraindicated in both arms except for low dose aspirin defined as 1-5 mg/Kg/day with maximum of 100 mg/day.
4. Administration of rifampin is prohibited during the study and subjects on concomitant use of rifampin are excluded.
5. Subjects with hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk (aPTT > 50 seconds or international normalized ratio [INR] > 2.0 not related to anticoagulation therapy) or alanine aminotransferase (ALT) > 5 × the upper limit of normal (ULN) or total bilirubin > 2 × ULN with direct bilirubin > 20% of the total at Screening Visit.
6. Subjects with glomerular filtration rate (GFR) < 30% of normal for age and size as determined by the Schwartz formula.
7. Subjects with stage 2 hypertension defined as blood pressure (BP) systolic and/or diastolic confirmed > 99th percentile + 5 mmHg.
8. Subject with thrombocytopenia < 50 × 109/L at Screening Visit. Subjects with a history of heparin-induced thrombocytopenia may be enrolled in the study at the Investigator's discretion.
9. Life expectancy less than the expected study treatment duration (3 months).
10. Subjects who are known to be pregnant or breastfeeding.
11. Subjects with any condition that, as judged by the Investigator, would place the subject at increased risk of harm if he/she participated in the study, including contraindicated medications.
12. Subjects who participated in another clinical study or treated with an experimental therapy with less than a 30 day washout period prior to identifying the qualifying index VTE.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Edoxaban; Edoxaban treatment will be dispensed to the participant on a monthly visit schedule. Edoxaban will be started orally at the age/weight/renal function appropriate dose, depending on the results of the ongoing U157 study (NCT02303431) for the Treatment Period.	Drug: Edoxaban; 15 or 30 mg tablets for participants 12 years of age to <18, and 60 mg edoxaban suspension for oral administration to participants under 12 years of age
Experimental: Standard of Care; Standard of Care (SOC) treatment will be dispensed to the participant on a monthly visit schedule.	Drug: Standard of Care; Standard of care could include low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors.; Other Names: Warfarin/heparin; Enoxaparin; Fondaparinux

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	Diagnosis of recurrent venous thromboembolism (VTE) requires the confirmation by diagnostic imaging and at least one of the symptoms of VTE from such areas as lower or upper extremity, catheter related thrombosis, pulmonary embolism, or sinovenous thrombosis.	Randomization to Month 3
Number of Participants Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	Death from venous thromboembolism (VTE) is based on objective diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out.	Randomization to Month 3
Number of Participants With No Change or Extension of Thrombotic Burden During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	No change or extension of thrombotic burden as assessed by quantitative diagnostic imaging of the index qualifying VTE thrombus at baseline and at Month 3. Imaging criteria for VTE included: - Abnormal compression ultrasonography where compression had been normal or, if non-compressible during screening, an increase in diameter of the thrombus during full compression; - An extension of the echogenic intra-luminal thrombus or absence of flow in the central venous system on Doppler ultrasonography. - An extension of an intraluminal filling defect, or a new intraluminal filling defect, or an extension of non-visualization of veins in the presence of a sudden cut-off on venography. - An extension of an intraluminal filling defect, or a new intraluminal filling defect on computed tomography angiogram (CTA).	Randomization to Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Symptomatic Recurrent Venous Thromboembolism During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	Diagnosis of recurrent venous thromboembolism (VTE) requires the confirmation by diagnostic imaging and at least one of the symptoms of VTE from such areas as lower or upper extremity, catheter related thrombosis, pulmonary embolism, or sinovenous thrombosis.	From randomization up to Month 12
Number of Participants With Symptomatic Recurrent VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)	Diagnosis of recurrent venous thromboembolism (VTE) requires the confirmation by diagnostic imaging and at least one of the symptoms of VTE from such areas as lower or upper extremity, catheter related thrombosis, pulmonary embolism, or sinovenous thrombosis.	Randomization to Month 3
Number of Participants Who Died as a Result of VTE During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	Death from venous thromboembolism (VTE) is based on objective diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out.	From randomization up to Month 12
Number of Participants Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)	Death from venous thromboembolism (VTE) is based on objective diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out.	Randomization to Month 3
Number of Participants With No Change or Extension of Thrombotic Burden During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	No change or extension of thrombotic burden as assessed by quantitative diagnostic imaging of the index qualifying VTE thrombus. Imaging criteria for VTE included: - Abnormal compression ultrasonography where compression had been normal or, if non-compressible during screening, an increase in diameter of the thrombus during full compression; - An extension of the echogenic intra-luminal thrombus or absence of flow in the central venous system on Doppler ultrasonography. - An extension of an intraluminal filling defect, or a new intraluminal filling defect, or an extension of non-visualization of veins in the presence of a sudden cut-off on venography. - An extension of an intraluminal filling defect, or a new intraluminal filling defect on computed tomography angiogram (CTA).	From randomization up to Month 12
Number of Participants With Adjudicated Individual Component of Primary Efficacy Endpoints During the Main Treatment Period Following Edoxaban or Standard of Care Treatment	Diagnosis of recurrent VTE requires the confirmation imaging and ≥1 symptom of VTE. Death from VTE is based on diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out. No change or extension of thrombotic burden (quantitative diagnostic imaging) of the index qualifying VTE thrombus. Imaging criteria for VTE: - Abnormal compression ultrasonography where compression had been normal or, if non-compressible during screening, an increase in diameter of the thrombus during full compression; - An extension of the echogenic intra-luminal thrombus or absence of flow in the central venous system on Doppler ultrasonography. - An extension of an intraluminal filling defect, or a new intraluminal filling defect, or an extension of non-visualization of veins in the presence of a sudden cut-off on venography. - An extension of an intraluminal filling defect, or a new intraluminal filling defect on computed tomography angiogram (CTA).	Randomization to Month 3
Number of Participants Reporting Adjudicated All-Cause Mortality During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated)	All-cause mortality is defined as death due to any cause. Adjudicated data are reported for overall all-cause mortality, all-cause mortality by the primary cause of death, and primary cause of death further described by additional specifications.	From randomization up to Month 12
Number of Participants With Deep Vein Thrombosis, Catheter-related Thrombosis, Sino-venous Thrombosis, and Pulmonary Embolism During the Main, Extension, and Overall Treatment Periods Following Edoxaban or Standard of Care Treatment	Deep vein thrombosis was assessed by ultrasonography or magnetic resonance venography (MRV), catheter-related thrombosis was assessed by ultrasonography or echocardiography, sino-venous thrombosis was assessed by brain MRI, and pulmonary embolism was assessed by nuclear ventilation/perfusion (V/Q) scanning.	From randomization up to Month 12
Number of Participants With Major and Clinically Relevant Non-Major Bleeding Events (On Treatment) During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	Any bleeding event defined as major and clinically relevant non-major bleeding (CRNM) events was reported. Major bleeding was defined as defined as a composite of any of the following: fatal bleeding; and/or symptomatic bleeding in critical area or organ such as intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular, pulmonary, or pericardial, or intramuscular with compartment syndrome; and/or bleeding that causes a decrease in hemoglobin of at least 2 g/dL or more, or leading to transfusion of the equivalent of two or more units of whole blood or red blood cells. CRNM was defined as acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding; a physician-guided medical or surgical treatment for bleeding or a change in antithrombotic therapy (including interruption or discontinuation of study drug).	Randomization to Month 3
Number of Participants With All Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	All bleeding events included major bleeding defined as a composite of any of the following: fatal bleeding; and/or symptomatic bleeding in critical area or organ such as intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular, pulmonary, or pericardial, or intramuscular with compartment syndrome; and/or bleeding that causes a decrease in hemoglobin of at least 2 g/dL or more, or leading to transfusion of the equivalent of two or more units of whole blood or red blood cells (RBCs), clinically relevant non-major bleeding defined as acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding; a physician-guided medical or surgical treatment for bleeding or a change in antithrombotic therapy (including interruption or discontinuation of study drug), nuisance bleeding, or a combination of bleeding events.	From randomization up to Month 12
Number of Participants With Major and Clinically Relevant Non-Major Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)	Any bleeding event defined as major and clinically relevant non-major bleeding (CRNM) events was reported. Major bleeding was defined as defined as a composite of any of the following: fatal bleeding; and/or symptomatic bleeding in critical area or organ such as intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular, pulmonary, or pericardial, or intramuscular with compartment syndrome; and/or bleeding that causes a decrease in hemoglobin of at least 2 g/dL or more, or leading to transfusion of the equivalent of two or more units of whole blood or red blood cells. CRNM was defined as acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding; a physician-guided medical or surgical treatment for bleeding or a change in antithrombotic therapy (including interruption or discontinuation of study drug).	From randomization up to Month 12

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Publications and helpful links

General Publications

• Hokusai-VTE Investigators; Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638. Epub 2013 Aug 31. Erratum In: N Engl J Med. 2014 Jan 23;370(4):390.

Helpful Links

• Related Information

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2017
• Primary Completion (Actual): May 24, 2022
• Study Completion (Actual): May 24, 2022

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: June 8, 2016
• First Posted (Estimate): June 14, 2016

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: February 3, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Pediatric; Venous thrombolism; Pulmonary embolism
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Thromboembolism; Venous Thromboembolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Heparin; Edoxaban; Enoxaparin; Warfarin; Fondaparinux
• Other Study ID Numbers: DU176b-D-U312; 2016-000991-49 (EudraCT Number); CTRI/2018/01/011249 (Registry Identifier: Clinical Trials Registry - India (CTRI)); NCT02798471 (Registry Identifier: ClinicalTrials.gov)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No