Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease

An Open-label, Randomised, Parallel-group, Multicentre, Observational Trial to Evaluate Safety and Efficacy of Edoxaban Tosylate in Children From 38 Weeks Gestational Age to Less Than 18 Years of Age With Cardiac Diseases at Risk of Thromboembolic Events

A committee will judge the safety and effectiveness of edoxaban and the regular treatment (standard of care).

All children in the study will receive free treatment. They will have a 2 in 3 chance to receive edoxaban, and a 1 in 3 chance to receive the standard of care for preventing blood clots.

The study will find out if edoxaban is safer and more effective than the standard of care.

Study Overview

• Status: Completed
• Conditions: Cardiac Disease
• Intervention / Treatment: Drug: Edoxaban; Drug: Standard of Care (SOC)

Detailed Description

The primary objective is to compare the safety of edoxaban with the standard of care (SOC) in pediatric subjects with cardiac diseases at risk of thromboembolic complications who need primary or secondary anticoagulant prophylaxis with regard to the combination of major and clinically relevant non-major (CRNM) bleeding per International Society on Thrombosis and Haemostasis [ISTH] definition.

The key secondary objective is to compare the efficacy of edoxaban against SOC with regard to the development of symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways including deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus and myocardial infarction (MI), and asymptomatic intracardiac thrombus identified by cardiac imaging.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum Med Campus IV
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1C5
      • CHU Sainte-Justine
    • Pierrefonds, Quebec, Canada, H9H 4Y6
      • McGill University Health Centre/Glen Site/Montreal Children's Hospital
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Center Zagreb
• Egypt
  • Alexandria, Egypt, 21131
    • Alexandria Clinical Research Center, Faculty of Medicine
  • Cairo, Egypt, 11562
    • Kasr Elainy School of Medicine, Abo Elreesh Hospital (Japanese Hospital), Ali Basha Ibrahim ST Faculty of Medicine Cairo University
  • Cairo, Egypt, 11566
    • Ain Shams University Hospital
  • Ismailia, Egypt, 41522
    • Suez Canal University Hospital
  • Al Sharkeya
    • Zagazig, Al Sharkeya, Egypt, 44519
      • Zagazig university hospital
• France
  • Haute Garonne
    • Toulouse cedex 9, Haute Garonne, France, 31059
      • Hôpital Des Enfants, Bâtiment Modulaire
  • Herault
    • Montpellier, Herault, France, 34295
      • Pediatric and Congenital Cardiology and Pulmonology Department; Arnaud De Villeneuve University Hospital
  • Paris Cedex 15
    • Paris, Paris Cedex 15, France, 75015
      • Pediatric Cardiology Department, Hospital Necker Enfants Malades, APHP, Université Paris Descartes
• Hungary
  • Budapest, Hungary, 1096
    • Gottsegen György Országos Kardiológiai Intézet
  • Szeged, Hungary, 6720
    • Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
• India
  • Kolkata, India, 700017
    • Institute of Child Health
  • Gujarat
    • Sūrat, Gujarat, India, 395002
      • Nirmal Hospital Private Limited
• Israel
  • Be'er Sheva, Israel, 8410101
    • Soroka University Medical Center
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital - Ein Kerem
  • Ramat Gan, Israel, 5265601
    • Sheba Medical Center
• Lebanon
  • Beirut, Lebanon, 166830
    • Hotel Dieu de France Hospital
  • Beirut, Lebanon, 11-0236
    • Children's Heart Centre at the American University of Beirut Medical Center
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe University Medical Faculty
  • Istanbul, Turkey, 34093
    • Istanbul University Istanbul Medical Faculty
  • İzmir, Turkey, 35040
    • Ege University Faculty of Medicine Department of Child Health and Diseases
  • İzmir, Turkey, 35210
    • Izmir-Dr. Behçet Uz. Pediatric Diseases and Surgery Training and Research Hospital- Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi
  • Kayseri
    • Edirne, Kayseri, Turkey, 38039
      • Erciyes University Medical Faculty, Department of Children Hospital
• Ukraine
  • Dnipro, Ukraine, 49100
    • Communal Institution Dnipropetrovsk Regional Pediatric Clinical Hospital of Dnipropetrovsk Regional Council, State Institution Dnipropetrovsk Medical Academy of MoH of Ukraine
  • Kharkiv, Ukraine, 61093
    • Communal Healthcare Institution Regional Pediatric Clinical Hospital, Kharkiv National Medical University
  • Vinnytsia, Ukraine, 21000
    • Vynnitsa Regional Children Clinical Hospital Policlinic Dept
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SW3 6HP
      • Royal Brompton Hospital
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Glenfield Hospital
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G51 4TF
      • Ward 2B, Royal Hospital for Children
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Mesa, Arizona, United States, 85202
      • Cardon Childrens Medical Center
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center (ECG)
    • San Francisco, California, United States, 94158
      • University of California-San Francisco Department of Pediatrics - Hematology/Oncology
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Heart and Vascular Institute
    • Greenville, North Carolina, United States, 27834
      • East Carolina Heart Institute @ ECU
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OU Health Sciences Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Research Institute

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:

• Is a child with cardiac disease who is at risk for thromboembolic complications and requires at least 3 months antithrombotic anticoagulant prophylaxis

Either one of the following:

1. a child with cardiac disease who has a history of cardiac shunt occlusion/thrombosis, with shunt still in place (secondary prevention).

   OR

2. a child with cardiac disease who requires (including those already taking, and those not yet taking) anticoagulation for primary prevention of TE.

Cardiac conditions known to significantly increase the risk of thrombosis (hence, indications for primary TE prevention) are defined in Antithrombotic Therapy and Prevention of Thrombosis. Some examples of cardiac conditions at risk of thrombosis are Fontan surgery, heart failure, Kawasaki disease, and Blalock-Taussig and Glenn surgery.

• Is a male or female child between 1 and <18 years of age (children between 38 weeks gestational age and 1 year of age will be included in the study, however, only after the safety and efficacy data of 50 subjects between 1 and <18 years of age in the edoxaban arm have been evaluated at the end of the 3-month treatment period)
• Has parent(s)/legal guardian(s) or legally acceptable representative who is informed and provides signed consent for the child, to participate in the study with edoxaban treatment. Pediatric participants with appropriate intellectual maturity will be required to sign an assent form in addition to the signed informed consent from the parent(s)/legal guardian(s) or any legally acceptable representative.
• If a female subject of childbearing potential, tests negative for pregnancy at Screening and consents to avoid becoming pregnant by using a locally approved contraception method throughout the study

Exclusion Criteria:

• Has evidence of symptomatic venous or arterial thrombosis and/or asymptomatic intracardiac thrombosis confirmed by a transthoracic echocardiogram during study screening period
• Has mechanical heart valve(s)
• Has active bleeding or high risk of bleeding contraindicating treatment with anticoagulant
• Takes antithrombotic therapy (other than low-dose aspirin) that is not protocol-related
• Administration of rifampin is prohibited during the study and subjects on concomitant use of rifampin are excluded
• Has any hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk
• Has estimated glomerular filtration rate (eGFR) <30% of normal for age and size
• Has stage 2 hypertension defined as blood pressure systolic and/or diastolic confirmed >99th percentile plus 5 mmHg
• Has thrombocytopenia or life expectancy less than three months
• Has had Fontan procedure with a history of or signs/symptoms suggestive of protein-losing enteropathy
• Is pregnant or breastfeeding
• Has a contraindication to the use of heparin and/or vitamin K antagonist (VKA)
• Has any condition that, as judged by the Investigator, would place the participant at increased risk of harm if he/she participated in the study, including contraindicated medications identified in the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Edoxaban; Two out of three participants will be randomized for treatment with edoxaban solution or tablets	Drug: Edoxaban; Edoxaban 15 mg or 30 mg tablets for participants 12 to <18 years of age, or 60 mg edoxaban suspension (dosed as mg/kg) for participants under 12 years of age (and optionally, 12 or older), for oral administration; Other Names: Lixiana; Savaysa
Active Comparator: Standard of Care (SOC); One out of three participants will be randomized for treatment with the institution's SOC regimen	Drug: Standard of Care (SOC); Standard of care could include low molecular weight heparin (LMWH) and/or VKA according to the clinical site's SOC treatment regimen; Other Names: Warfarin/heparin; Enoxaparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adjudicated Bleeding Events Within the Main Treatment Period	Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an 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, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding.	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways Within the Main Treatment Period	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
Number of Participants Who Died as a Result of Thromboembolic Event Within the Main Treatment Period	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) Within the Main Treatment Period	Death due to any cause (all-cause mortality) was assessed.	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
Number of Participants With Adjudicated Bleeding Events During the Extension Period	Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an 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, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding.	Month 4 up to Month 13
Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways During the Extension Period	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).	Month 4 up to Month 13
Number of Participants Who Died as a Result of Thromboembolic Event During the Extension Period	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).	Month 4 up to Month 13
Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) During the Extension Period	Death due to any cause (all-cause mortality) was assessed.	Month 4 up to Month 13

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2018
• Primary Completion (Actual): December 3, 2021
• Study Completion (Actual): December 3, 2021

Study Registration Dates

• First Submitted: January 4, 2018
• First Submitted That Met QC Criteria: January 4, 2018
• First Posted (Actual): January 10, 2018

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 5, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Children; Pediatrics; Prophylactic treatment; Cardiac disease with potential for thromboembolic complications; Anticoagulant drugs
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; 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
• Other Study ID Numbers: DU176b-C-U313; 2017-000475-90 (EudraCT Number)

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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

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