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

Pulmonary Embolism Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02798471
• Other study ID #: DU176b-D-U312
• Secondary ID: 2016-000991-49CT
• Status: Completed
• Phase: Phase 3
• Start date: March 27, 2017
• Est. completion date: May 24, 2022

Study information

• Verified date: February 2023
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 290
• Est. completion date: May 24, 2022
• Est. primary completion date: May 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Bulgaria,  Canada,  Chile,  Croatia,  Czechia,  Denmark,  El Salvador,  France,  Germany,  Guatemala,  Hungary,  India,  Israel,  Kenya,  Korea, Republic of,  Lebanon,  Malaysia,  Netherlands,  Norway,  Panama,  Portugal,  Romania,  Russian Federation,  Serbia,  Singapore,  Slovenia,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine, 

References & 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. Erratum In: N Engl J Med. 2014 Jan 23;370(4):390. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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