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

Cardiac Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03395639
• Other study ID #: DU176b-C-U313
• Secondary ID: 2017-000475-90
• Status: Completed
• Phase: Phase 3
• Start date: May 15, 2018
• Est. completion date: December 3, 2021

Study information

• Verified date: July 2022
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 168
• Est. completion date: December 3, 2021
• Est. primary completion date: December 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiac Disease
• Heart Diseases

Intervention

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
• 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

Locations

Country	Name	City	State
Austria	Kepler Universitätsklinikum Med Campus IV	Linz
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	CHU Sainte-Justine	Montréal	Quebec
Canada	McGill University Health Centre/Glen Site/Montreal Children's Hospital	Pierrefonds	Quebec
Croatia	University Hospital Center Zagreb	Zagreb
Egypt	Alexandria Clinical Research Center, Faculty of Medicine	Alexandria
Egypt	Ain Shams University Hospital	Cairo
Egypt	Kasr Elainy School of Medicine, Abo Elreesh Hospital (Japanese Hospital), Ali Basha Ibrahim ST Faculty of Medicine Cairo University	Cairo
Egypt	Suez Canal University Hospital	Ismailia
Egypt	Zagazig University Hospital	Zagazig	Al Sharkeya
France	Pediatric and Congenital Cardiology and Pulmonology Department; Arnaud De Villeneuve University Hospital	Montpellier	Herault
France	Pediatric Cardiology Department, Hospital Necker Enfants Malades, APHP, Université Paris Descartes	Paris	Paris Cedex 15
France	Hôpital Des Enfants, Bâtiment Modulaire	Toulouse cedex 9	Haute Garonne
Hungary	Gottsegen Gyorgy Orszagos Kardiologiai Intezet	Budapest
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged
India	Institute of Child Health	Kolkata
India	Nirmal Hospital Private Limited	Surat	Gujarat
Israel	Soroka University Medical Center	Be'er Sheva
Israel	Hadassah University Hospital - Ein Kerem	Jerusalem
Israel	Sheba Medical Center	Ramat Gan
Lebanon	Children's Heart Centre at the American University of Beirut Medical Center	Beirut
Lebanon	Hotel Dieu de France Hospital	Beirut
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Erciyes University Medical Faculty, Department of Children Hospital	Edirne	Kayseri
Turkey	Istanbul University Istanbul Medical Faculty	Istanbul
Turkey	Ege University Faculty of Medicine Department of Child Health and Diseases	Izmir
Turkey	Izmir-Dr. Behçet Uz. Pediatric Diseases and Surgery Training and Research Hospital- Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi	Izmir
Ukraine	Communal Institution Dnipropetrovsk Regional Pediatric Clinical Hospital of Dnipropetrovsk Regional Council, State Institution Dnipropetrovsk Medical Academy of MoH of Ukraine	Dnipro
Ukraine	Communal Healthcare Institution Regional Pediatric Clinical Hospital, Kharkiv National Medical University	Kharkiv
Ukraine	Vynnitsa Regional Children Clinical Hospital Policlinic Dept	Vinnytsia
United Kingdom	Ward 2B, Royal Hospital for Children	Glasgow	Strathclyde
United Kingdom	Glenfield Hospital	Leicester	Leicestershire
United Kingdom	Royal Brompton Hospital	London	Greater London
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Novant Health Heart and Vascular institute	Charlotte	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Florida College of Medicine	Gainesville	Florida
United States	East Carolina Heart Institute @ ECU	Greenville	North Carolina
United States	Cedars Sinai Medical Center (ECG)	Los Angeles	California
United States	Cardon Childrens Medical Center	Mesa	Arizona
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	OU Health Sciences Center	Oklahoma City	Oklahoma
United States	University of California-San Francisco Department of Pediatrics - Hematology/Oncology	San Francisco	California
United States	Seattle Children's Research Institute	Seattle	Washington
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Croatia,  Egypt,  France,  Hungary,  India,  Israel,  Lebanon,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

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