Clinical trial NCT02798471: Hokusai Study in Pediatric Patients With Confirmed Venous Thromboembolism (VTE)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Venous Thromboembolism (VTE)
Pulmonary Embolism
Deep Vein Thrombosis (DVT)
Keywords: Pediatric
Venous thrombolism
Pulmonary embolism
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2016-06-14
Enrollment: 290
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
timeFrame: Randomization to Month 3
measure: Number of Participants Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
timeFrame: Randomization to Month 3
measure: 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)
timeFrame: Randomization to Month 3
Secondary outcomes:
measure: Number of Participants With Symptomatic Recurrent Venous Thromboembolism During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
timeFrame: From randomization up to Month 12
measure: 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)
timeFrame: Randomization to Month 3
measure: Number of Participants Who Died as a Result of VTE During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
timeFrame: From randomization up to Month 12
measure: 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)
timeFrame: Randomization to Month 3
measure: 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)
timeFrame: From randomization up to Month 12
measure: Number of Participants With Adjudicated Individual Component of Primary Efficacy Endpoints During the Main Treatment Period Following Edoxaban or Standard of Care Treatment
timeFrame: Randomization to Month 3
measure: Number of Participants Reporting Adjudicated All-Cause Mortality During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated)
timeFrame: From randomization up to Month 12
measure: 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
timeFrame: From randomization up to Month 12
measure: 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)
timeFrame: Randomization to Month 3
measure: Number of Participants With All Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
timeFrame: From randomization up to Month 12
measure: 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)
timeFrame: From randomization up to Month 12
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center CAR
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Children's Hospital-Oak Lawn
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Hemophilia and Thrombosis Center
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Grand Rapids
country: United States
facility: Spectrum Health Helen DeVos Children's Hospital Grand Rapids
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital & Clinics of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: University North Carolina- Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Levine Children's Hospital Charlotte
state: North Carolina
city: Charlotte
country: United States
facility: The Presbyterian Hospital
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Memphis
country: United States
facility: Le Bonheur Childrens Hospital
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Hospital Italiano Regional del Sur
city: Cordoba
country: Argentina
facility: Sanatorio Allende
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer
state: Paraná
city: Pernambuco
country: Brazil
facility: IMIP - Instituto de Medicina Integral Professor Fernando Figueira
state: Recife
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
state: Rio Grande Do Sul
city: Passo Fundo
country: Brazil
facility: Hospital da Cidade de Passo Fundo
state: Rio Grande Do Sul
city: Pôrto Alegre
country: Brazil
facility: Instituto de Cardiologia do Rio Grande do Sul
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Hospital de Câncer de Barretos - Fundação Pio XII
state: São Paulo
city: Campinas
country: Brazil
facility: Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP
state: São Paulo
city: Santo André
country: Brazil
facility: Centro Multidisciplinar de Estudos Clínicos - CEMEC
state: São Paulo
city: Votuporanga
country: Brazil
facility: Santa Casa de Votuporanga
state: São Paulo
city: São Paulo
country: Brazil
facility: Hospital Samaritano
city: São Paulo
country: Brazil
facility: Hospital da Luz Amico Saude LTDA
city: São Paulo
country: Brazil
facility: Hospital Infantil Pequeno Príncipe
city: São Paulo
country: Brazil
facility: GRAACC - Grupo de Apoio ao Adolescente e à Criança com Câncer
city: São Paulo
country: Brazil
facility: UNIFESP - Universidade Federal de São Paulo
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
city: São Paulo
country: Brazil
facility: HMCG - Hospital e Maternidade Dr. Christovão da Gama
city: Plovdiv
country: Bulgaria
facility: UMHAT "Sv. Georgi", EAD
city: Sofia
country: Bulgaria
facility: MHAT - "National Heart Hospital" EAD
city: Sofia
country: Bulgaria
facility: MHAT 'Tokuda Hospital Sofia', EAD
city: Sofia
country: Bulgaria
facility: Medical Center for Specialized Ambulatory Medical Assistance for Children's Diseases
city: Edmonton
country: Canada
facility: Edmonton Clinic Health Academy
state: Alberta
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: Maipu
country: Chile
facility: Hospital El Carmen Dr. Luis Valentin Ferrada
city: Santiago
country: Chile
facility: Clinica Las Condes
city: Rijeka
country: Croatia
facility: Clinical Hospital Centre Rijeka
city: Zadar
country: Croatia
facility: General Hospital Zadar
city: Zagreb
country: Croatia
facility: Children's Hospital Zagreb
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb, University of Zagreb School of Medicine
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hodonin
country: Czechia
facility: CTC Hodonin s.r.o.
city: Hradec Králové
country: Czechia
facility: Dětská klinika Fakultní nemocnice
city: Plzen
country: Czechia
facility: University Hospital Pilsen, CZ
city: Aalborg
country: Denmark
facility: Ålborg Universitetshospital
city: San Salvador
country: El Salvador
facility: Hospital Nacional de Niños Benjamín Bloom
state: Salvador
city: Brest
country: France
facility: Clinical Hospital Centre Cavale Blanche BREST
state: Finistere
city: Pessac
country: France
facility: Groupe Hospitalier Sud - Hôpital Haut-Lévêque
state: Gironde
city: Toulouse
country: France
facility: Hôpital des enfants, CHU Toulouse
state: Haute Garonne
city: Rennes
country: France
facility: CHU Rennes - Hopital Sud
state: Ille Et Vilaine
city: Angers
country: France
facility: CHU Angers - Hôpital Hôtel Dieu
city: Clermont-Ferrand
country: France
facility: CHU Clermont Ferrand - Hôpital d'Estaing
city: Montpellier
country: France
facility: CHU Arnaud de Villeneuve
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein Westfalen
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum
city: Guatemala
country: Guatemala
facility: Unidad de Cirugía Cardiovascular de Guatemala (UNICAR)
city: Guatemala
country: Guatemala
facility: Unidad Nacional de Oncología Pediátrica (UNOP)
city: Budapest
country: Hungary
facility: Semmelweis University 2nd Department of Pediatrics
city: Budapest
country: Hungary
facility: Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
city: Szeged
country: Hungary
facility: University of Szeged, Department of Pediatrics
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
state: Delhi
city: Karamsad
country: India
facility: Shree Krishna Hospital & Medical Research Centre, H M Patel Centre for Medical Care and Education
state: Gujarat
city: Surat
country: India
facility: Nirmal Hospital
state: Gujarat
city: Bangalore
country: India
facility: Jain Institute of Vascular Sciences
state: Karnataka
city: Bangalore
country: India
facility: M. S. Ramaiah Medical College and Hospital
state: Karnataka
city: Nagpur
country: India
facility: Government Medical College and Hospital
state: Maharashtra
city: Ludhiana
country: India
facility: Christian Medical College
state: Punjab
city: Kolkata
country: India
facility: Institute of Child Health
state: West Bengal
city: Delhi
country: India
facility: Indraprastha Apollo Hospitals
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah ein Kerem
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Nairobi
country: Kenya
facility: Strathmore University Medical Centre
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Beirut
country: Lebanon
facility: American University of Beirut Medical Center
city: Beirut
country: Lebanon
facility: Saint George University Hospital Medical Center
city: Beirut
country: Lebanon
facility: Hotel Dieu de France Hospital
city: Kota Bharu
country: Malaysia
facility: Hospital Raja Perempuan Zainab II
state: Kelantan
city: Rotterdam
country: Netherlands
facility: Erasmus MC Sophia
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Panamá
country: Panama
facility: INDICASAT AIP Site 7871
city: Panamá
country: Panama
facility: INDICASAT AIP Site 7872
city: Braga
country: Portugal
facility: Hospital de Braga
city: Guimarães
country: Portugal
facility: Hospital da Senhora da Oliveira
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santa Marta
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria
city: Sângeorgiu De Mureş
country: Romania
facility: S.C Centrul Clinic Mediquest S.R.L
city: Kirov
country: Russian Federation
facility: FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion, FMBA"
city: Moscow
country: Russian Federation
facility: Russian Scientific Center of Radiology and Nuclear Medicine of Ministry of Health of Russian Federation, Department of Pediatric Oncology
city: Belgrade
country: Serbia
facility: Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic"
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: KK Women's And Children's Hospital
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Vitoria
country: Spain
facility: Hospital Universitario Araba
state: Álava
city: Hualien City
country: Taiwan
facility: Buddhist Tzu Chi General Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Veterans General Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei City
country: Taiwan
facility: Taipei Medical University Hospital
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Phramongkutklao Hospital
city: Chiang Mai
country: Thailand
facility: Chiang Mai University Hospital, Faculty of Medicine, Chiang Mai University
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Songkhla
country: Thailand
facility: Songklanagarind Hospital
city: Adana
country: Turkey
facility: Cukurova University Faculty of Medicine Balcali Hospital Pediatry Department
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Ankara Çocuk Sağlığı Ve Hastalıkları Hematoloji Onkoloji Eğitim Araştırma Hastanesi
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty
city: Istanbul
country: Turkey
facility: Yeditepe University Oncology Hospital
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Izmir
country: Turkey
facility: Izmir Tepecik Training and Research Hospital
city: Izmir
country: Turkey
facility: Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi
city: Kayseri
country: Turkey
facility: Erciyes University Medical Faculty
city: Mersin
country: Turkey
facility: Mersin University Health Research and Practice Hospital
city: Dnipro
country: Ukraine
facility: Regional Children's Clinical Hospital
city: Kharkiv
country: Ukraine
facility: CI of Healthcare Regional Children CH Gastroenterology Center Kharkiv NMU
city: Poltava
country: Ukraine
facility: Children City Clinical Hospital
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References:
citation: 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.