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

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.

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