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

NCT02798471 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: DU176b-D-U3122016-000991-49CTRI/2018/01/011249NCT02798471
• Study Type: interventional
• Target: 290
• Locations: 34 countries
• Sites: 140

Brief Summary

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.

Conditions

Venous Thromboembolism (VTE); Pulmonary Embolism; Deep Vein Thrombosis (DVT)

Keywords

Pediatric; Venous thrombolism; Pulmonary embolism

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (11)

• Number of Participants With Symptomatic Recurrent Venous Thromboembolism During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

  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)

  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)

  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)

  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)

  From randomization up to Month 12

Study Arms (2)

Edoxaban

EXPERIMENTAL

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

Standard of Care

EXPERIMENTAL

Standard of Care (SOC) treatment will be dispensed to the participant on a monthly visit schedule.

Drug: Standard of Care

Interventions

Edoxaban DRUG

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

Edoxaban

Standard of Care DRUG

Standard of care could include low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors.

Also known as: Warfarin/heparin, Enoxaparin, Fondaparinux

Standard of Care

Eligibility Criteria

• Age: 1 Day - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• Pediatric subjects with the presence of documented VTE confirmed by appropriate diagnostic imaging and requiring anticoagulant therapy for at least 90 days.
• 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.
• 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.
• 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.

You may not qualify if:

• 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).
• Subjects who have been or are being treated with thrombolytic agents, thrombectomy or insertion of a caval filter for the newly identified index VTE.
• 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.
• Administration of rifampin is prohibited during the study and subjects on concomitant use of rifampin are excluded.
• 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.
• Subjects with glomerular filtration rate (GFR) \< 30% of normal for age and size as determined by the Schwartz formula.
• Subjects with stage 2 hypertension defined as blood pressure (BP) systolic and/or diastolic confirmed \> 99th percentile + 5 mmHg.
• 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.
• Life expectancy less than the expected study treatment duration (3 months).
• Subjects who are known to be pregnant or breastfeeding.
• 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.
• 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.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (140)

Banner University Medical Center

Tucson, Arizona, 85724, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

UCLA Medical Center CAR

Los Angeles, California, 90095, United States

Location

Stanford University Medical Center

Stanford, California, 94305, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Advocate Children's Hospital-Oak Lawn

Oak Lawn, Illinois, 60453, United States

Location

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, 46260, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Spectrum Health Helen DeVos Children's Hospital Grand Rapids

Grand Rapids, Michigan, 49503, United States

Location

Children's Hospital & Clinics of Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University North Carolina- Chapel Hill

Chapel Hill, North Carolina, 27517, United States

Location

Levine Children's Hospital Charlotte

Charlotte, North Carolina, 28204, United States

Location

The Presbyterian Hospital

Charlotte, North Carolina, 28210, United States

Location

East Carolina University

Greenville, North Carolina, 27858, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Hasbro Children's Hospital

Providence, Rhode Island, 02903, United States

Location

Le Bonheur Childrens Hospital

Memphis, Tennessee, 38105, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Hospital Italiano Regional del Sur

Buenos Aires, B8001HXM, Argentina

Location

Sanatorio Allende

Córdoba, X5000JHQ, Argentina

Location

Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer

Curitiba, Paraná, 81520-060, Brazil

Location

IMIP - Instituto de Medicina Integral Professor Fernando Figueira

Pernambuco, Recife, 50070-550, Brazil

Location

Hospital São Vicente de Paulo

Passo Fundo, Rio Grande do Sul, 99010-080, Brazil

Location

Hospital da Cidade de Passo Fundo

Passo Fundo, Rio Grande do Sul, 99010-260, Brazil

Location

Instituto de Cardiologia do Rio Grande do Sul

Pôrto Alegre, Rio Grande do Sul, 90620-001, Brazil

Location

Hospital de Câncer de Barretos - Fundação Pio XII

Barretos, São Paulo, 14784-400, Brazil

Location

Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP

Campinas, São Paulo, 13083-878, Brazil

Location

Centro Multidisciplinar de Estudos Clínicos - CEMEC

Santo André, São Paulo, 09190-510, Brazil

Location

Santa Casa de Votuporanga

Votuporanga, São Paulo, 15500-003, Brazil

Location

Hospital Samaritano

São Paulo, 01232-010, Brazil

Location

Hospital da Luz Amico Saude LTDA

São Paulo, 04013-060, Brazil

Location

Hospital Infantil Pequeno Príncipe

São Paulo, 04013-060, Brazil

Location

GRAACC - Grupo de Apoio ao Adolescente e à Criança com Câncer

São Paulo, 04039-001, Brazil

Location

UNIFESP - Universidade Federal de São Paulo

São Paulo, 04039-032, Brazil

Location

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

São Paulo, 05403-000, Brazil

Location

HMCG - Hospital e Maternidade Dr. Christovão da Gama

São Paulo, 09030-010, Brazil

Location

UMHAT "Sv. Georgi", EAD

Plovdiv, 4000, Bulgaria

Location

MHAT - "National Heart Hospital" EAD

Sofia, 1309, Bulgaria

Location

MHAT 'Tokuda Hospital Sofia', EAD

Sofia, 1407, Bulgaria

Location

Medical Center for Specialized Ambulatory Medical Assistance for Children's Diseases

Sofia, 1612, Bulgaria

Location

Edmonton Clinic Health Academy

Edmonton, Alberta, T6G 2B7, Canada

Location

CancerCare Manitoba

Winnipeg, Manitoba, R3E 0V9, Canada

Location

McMaster Children's Hospital

Hamilton, Ontario, L8N 3Z5, Canada

Location

Hospital El Carmen Dr. Luis Valentin Ferrada

Maipú, 9251521, Chile

Location

Clinica Las Condes

Santiago, 7591047, Chile

Location

Clinical Hospital Centre Rijeka

Rijeka, 51000, Croatia

Location

General Hospital Zadar

Zadar, 23000, Croatia

Location

Children's Hospital Zagreb

Zagreb, 10 000, Croatia

Location

University Hospital Centre Zagreb, University of Zagreb School of Medicine

Zagreb, 10000, Croatia

Location

Fakultni nemocnice Brno

Brno, 613 00, Czechia

Location

CTC Hodonin s.r.o.

Hodonín, 69501, Czechia

Location

Dětská klinika Fakultní nemocnice

Hradec Králové, 500 05, Czechia

Location

University Hospital Pilsen, CZ

Pilsen, 305 99, Czechia

Location

Ålborg Universitetshospital

Aalborg, 9000, Denmark

Location

Hospital Nacional de Niños Benjamín Bloom

San Salvador, Salvador, El Salvador

Location

Clinical Hospital Centre Cavale Blanche BREST

Brest, Finistere, 29200, France

Location

Groupe Hospitalier Sud - Hôpital Haut-Lévêque

Pessac, Gironde, 33600, France

Location

Hôpital des enfants, CHU Toulouse

Toulouse, Haute Garonne, 31059, France

Location

CHU Rennes - Hopital Sud

Rennes, Ille Et Vilaine, 35203, France

Location

CHU Angers - Hôpital Hôtel Dieu

Angers, 49100, France

Location

CHU Clermont Ferrand - Hôpital d'Estaing

Clermont-Ferrand, 63003, France

Location

CHU Arnaud de Villeneuve

Montpellier, 34295, France

Location

Universitaetsklinikum Essen

Essen, North Rhine-Westphalia, 45122, Germany

Location

Charite - Campus Virchow-Klinikum

Berlin, 13353, Germany

Location

Unidad de Cirugía Cardiovascular de Guatemala (UNICAR)

Guatemala City, Guatemala

Location

Unidad Nacional de Oncología Pediátrica (UNOP)

Guatemala City, Guatemala

Location

Semmelweis University 2nd Department of Pediatrics

Budapest, 1094, Hungary

Location

Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases

Budapest, H-1097, Hungary

Location

Debreceni Egyetem Klinikai Kozpont

Debrecen, 4032, Hungary

Location

University of Szeged, Department of Pediatrics

Szeged, 6720, Hungary

Location

Shree Krishna Hospital & Medical Research Centre, H M Patel Centre for Medical Care and Education

Karamsad, Gujarat, 388325, India

Location

Nirmal Hospital

Surat, Gujarat, 395002, India

Location

Jain Institute of Vascular Sciences

Bangalore, Karnataka, 560052, India

Location

M. S. Ramaiah Medical College and Hospital

Bangalore, Karnataka, 560054, India

Location

Government Medical College and Hospital

Nagpur, Maharashtra, 440003, India

Location

Sir Ganga Ram Hospital

New Delhi, National Capital Territory of Delhi, 110060, India

Location

Christian Medical College

Ludhiana, Punjab, 141008, India

Location

Institute of Child Health

Kolkata, West Bengal, 700017, India

Location

Indraprastha Apollo Hospitals

Delhi, 110076, India

Location

Rambam Medical Center

Haifa, 3109601, Israel

Location

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

Location

Hadassah ein Kerem

Jerusalem, 91120, Israel

Location

Chaim Sheba Medical Center

Ramat Gan, 52621, Israel

Location

Strathmore University Medical Centre

Nairobi, 59857-00200, Kenya

Location

American University of Beirut Medical Center

Beirut, 1107 2020, Lebanon

Location

Saint George University Hospital Medical Center

Beirut, 166378, Lebanon

Location

Hotel Dieu de France Hospital

Beirut, 166830, Lebanon

Location

Hospital Raja Perempuan Zainab II

Kota Bharu, Kelantan, 15586, Malaysia

Location

Erasmus MC Sophia

Rotterdam, 3000 CB, Netherlands

Location

Oslo University Hospital

Oslo, 15-274, Norway

Location

INDICASAT AIP Site 7871

Panama City, 0843-01103, Panama

Location

INDICASAT AIP Site 7872

Panama City, 0843-01103, Panama

Location

Hospital de Braga

Braga, 4710-243, Portugal

Location

Hospital da Senhora da Oliveira

Guimarães, 4835-044, Portugal

Location

Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santa Marta

Lisbon, 1169-1024, Portugal

Location

Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

S.C Centrul Clinic Mediquest S.R.L

Sângeorgiu de Mureş, 547530, Romania

Location

FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion, FMBA"

Kirov, 610027, Russia

Location

Russian Scientific Center of Radiology and Nuclear Medicine of Ministry of Health of Russian Federation, Department of Pediatric Oncology

Moscow, 117997, Russia

Location

Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic"

Belgrade, 11070, Serbia

Location

Clinical Center Kragujevac

Kragujevac, 34000, Serbia

Location

National University Hospital

Singapore, 119074, Singapore

Location

KK Women's And Children's Hospital

Singapore, 229899, Singapore

Location

University Medical Centre Ljubljana

Ljubljana, 1000, Slovenia

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Seoul National University Hospital

Seoul, 3080, South Korea

Location

Severance Hospital, Yonsei University

Seoul, 3722, South Korea

Location

Samsung Medical Center

Seoul, 6351, South Korea

Location

Hospital Universitari Vall d'Hebron

Barcelona, 8035, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

Location

Hospital Universitario Araba

Vitoria-Gasteiz, Álava, 01009, Spain

Location

Buddhist Tzu Chi General Hospital

Hualien City, 970, Taiwan

Location

Kaohsiung Veterans General Hospital

Kaohsiung City, 81362, Taiwan

Location

China Medical University Hospital

Taichung, 40447, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 40705, Taiwan

Location

Taipei Medical University Hospital

Taipei, 11031, Taiwan

Location

Ramathibodi Hospital

Bangkok, 10300, Thailand

Location

King Chulalongkorn Memorial Hospital

Bangkok, 10330, Thailand

Location

Phramongkutklao Hospital

Bangkok, 10400, Thailand

Location

Chiang Mai University Hospital, Faculty of Medicine, Chiang Mai University

Chiang Mai, 50200, Thailand

Location

Srinagarind Hospital

Khon Kaen, 40002, Thailand

Location

Songklanagarind Hospital

Songkhla, 90110, Thailand

Location

Cukurova University Faculty of Medicine Balcali Hospital Pediatry Department

Adana, 1330, Turkey (Türkiye)

Location

Hacettepe University Medical Faculty

Ankara, 6100, Turkey (Türkiye)

Location

Ankara Çocuk Sağlığı Ve Hastalıkları Hematoloji Onkoloji Eğitim Araştırma Hastanesi

Ankara, 6110, Turkey (Türkiye)

Location

Istanbul University Istanbul Medical Faculty

Istanbul, 34093, Turkey (Türkiye)

Location

Yeditepe University Oncology Hospital

Istanbul, 34718, Turkey (Türkiye)

Location

Ege University Medical Faculty

Izmir, 35040, Turkey (Türkiye)

Location

Izmir Tepecik Training and Research Hospital

Izmir, 35170, Turkey (Türkiye)

Location

Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi

Izmir, 35210, Turkey (Türkiye)

Location

Erciyes University Medical Faculty

Kayseri, 38039, Turkey (Türkiye)

Location

Mersin University Health Research and Practice Hospital

Mersin, 33343, Turkey (Türkiye)

Location

Regional Children's Clinical Hospital

Dnipro, 49100, Ukraine

Location

CI of Healthcare Regional Children CH Gastroenterology Center Kharkiv NMU

Kharkiv, 61093, Ukraine

Location

Children City Clinical Hospital

Poltava, 36004, Ukraine

Location

Related Publications (1)

• 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.

  PMID: 23991658 BACKGROUND

Related Links

• Related Information

MeSH Terms

Conditions

Venous Thromboembolism; Pulmonary Embolism; Venous Thrombosis

Interventions

edoxaban; Standard of Care; Warfarin; Heparin; Enoxaparin; Fondaparinux

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Embolism; Thrombosis

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Glycosaminoglycans; Polysaccharides; Carbohydrates; Heparin, Low-Molecular-Weight; Oligosaccharides

Results Point of Contact

• Title: Contact for Clinical Trial Information
• Organization: Daiichi Sankyo

CTRinfo@dsi.com

908-992-6400

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2016
• First Posted: June 14, 2016
• Study Start: March 27, 2017
• Primary Completion: May 24, 2022
• Study Completion: May 24, 2022
• Last Updated: February 28, 2025
• Results First Posted: March 6, 2023

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• 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.

Locations

NO (1); AR (2); DK (1); FR (7); KR (4); TU (10); PA (2); SL (1); UA (3); NL (1); PT (4); IL (4); SG (2); BU (4); TH (6); EL (1); KE (1); HU (4); LE (3); MY (1); CA (3); CL (2); IN (9); TW (5); RU (2); BR (16); CZ (4); DE (2); RO (1); SE (2); US (22); GU (2); ES (4); CR (4)