Conditions: Cardiac Disease
Keywords: Children Pediatrics Cardiac disease with potential for thromboembolic complications Prophylactic treatment Anticoagulant drugs
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 168
Healthy volunteers: no

Brief 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.

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.

Arms:
arm 1: Two out of three participants will be randomized for treatment with edoxaban solution or tablets arm 2: One out of three participants will be randomized for treatment with the institution's SOC regimen

Interventions: intervention 1: Edoxaban intervention 2: Standard of Care (SOC)
Intervention descriptions: intervention 1: 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 intervention 2: Standard of care could include low molecular weight heparin (LMWH) and/or VKA according to the clinical site's SOC treatment regimen

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
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. 
 
DU176b-C-U313 
 
IND NUMBER 63,266 
EUDRACT NUMBER 2017-000475-90 
 
VERSION 4.0, 03 JUN 2019 
VERSION 3.0, 27 MAR 2018 
VERSION 2.0 16 OCT 2017 
VERSION 1.0 27 JUN 2017 
 
DAIICHI SANKYO INC. 
211 MOUNT AIRY ROAD 
BASKING RIDGE, NJ 07920 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo Inc. The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement. Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo Inc. 




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GLOBAL AMENDMENT, PROTOCOL VERSION 4.0 
HIGH-LEVEL DESCRIPTION OF EACH CHANGE: RATIONALE AND LOCATION  
Changes to the Protocol: 
Please refer to the attached comparison document (tracked changes) of Clinical Study Protocol 
Version 3.0 (dated 27 Mar 2018) versus the Version 4.0 (dated 03 Jun 2019) for actual in-text 
changes. The summary of changes below is a high-level summary of major changes in the 
Clinical Study Protocol. 
High-Level Changes From Version 3.0 to Version 4.0 
Change 
Number 
Change Description 
1 
Addressed that the first dose of study treatment is not required to be on the same day 
of Randomization (Day 1) 
The following sections of the protocol were updated: 
 
Section 6.3 Randomization (Day 1, Visit 2) 
 
Table 17.1 Schedule of Events 
2 
Additional dosing details added for enoxaparin dosing in infants 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 5.2.1.2 Standard of Care Treatment Arm 
3 
Additional details added for edoxaban packaging for subjects 6 to <12 years old 
The following sections of the protocol were updated: 
 
Synopsis 
 
 
Section 5.2.1.1 Edoxaban (Randomization through Month 12) 


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Change 
Number 
Change Description 
4 
Modifications to Schedule of Events including the following: 
 
Row to add Interactive Web/Voice Response System transaction for 
Screening Visit and Visits 3 through 8 
 
Added body weight measurement at randomization 
 
Minor footnote clarifications to study drug dispensing and study drug 
compliance 
 
Clarified necessity of activated partial thromboplastin time and 
international normalized ratio (INR) assessments 
 
Footnote updated to collect PK samples at pre-dose and 1 to 3 hours post-
dose 
 
Clarified PD sample collection, 24-hour wash-out for pharmacodynamic 
assessments  
 
Moved pregnancy test from Screening Visit to Randomization and 
modified footnote 
The following sections of the protocol were updated: 
 
Table 17.1 Schedule of Events 
 
Section 6 Study Procedures 
 
Section 6.2 Screening/Qualification Visit (At Least Day -30 to Day 1, Visit 1) 
 
Section 6.3 Randomization (Day 1, Visit 2) 
 
Section 6.4.4 Month 3 (Visit 5; End of Main Treatment Period) Procedures 
 
Section 9.8.7 Urine Pregnancy Testing  
 
Appendix 17.3 Effective Methods of Birth Control 
5 
Modified lists of P-gp inducers and P-gp inhibitors 
The following sections of the protocol were updated: 
 
Appendix 17.5.6 P-gp Inducers (Prohibited Medication) 
 
Appendix 17.6.1 P-gp Inhibitors List 
6 
Removed adjudication timeline 
The following section of the protocol was updated: 
 
Section 6 Study Procedures 
7 
Permitted Screening and Randomization to occur on the same date 
The following sections of the protocol were updated: 
 
Section 6.2 Screening/Qualification Visit (At Least Day -30 to Day 1, Visit 1) 
 
Section 6.3 Randomization (Day 1, Visit 2)  
 
Table 17.1 Schedule of Events 


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Change 
Number 
Change Description 
8 
Allowed for use of local laboratory for Screening 
The following sections of the protocol were updated: 
 
Section 6.2 Screening/Qualification Visit (At Least Day -30 to Day 1, Visit 1) 
 
Section 9.8 Clinical Laboratory Evaluations 
 
Table 17.1 Schedule of Events 
9 
Update to treatment compliance (clarified procedures that only apply to edoxaban) 
The following section of the protocol was updated: 
 
Section 5.4 Method of Assessing Treatment Compliance 
10 
Update to drug accountability (when documentation should be appended to 
Certificate of Destruction) 
The following sections of the protocol were updated: 
 
Section 5.2.6.1 Edoxaban 
 
Section 5.2.6.2 Standard of Care 
11 
Removed 40-day requirement from prescription for locally sourced standard of care 
treatment. 
The following section of the protocol was updated: 
 
Section 6.3 Randomization 
12 
Corrected protocol number referenced in introduction, added minor updates  
The following sections of the protocol were updated: 
 
Section 1.2 Study Rationale 
 
Section 1.3 Risk/Benefit 
13 
Added inclusion criterion 5 (new requirements relating to history of TE) 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.1 Inclusion Criteria 
14 
Updated exclusion criterion 1 to replace “evidence” with “history” of the subsequent 
list of medical characteristics 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 
15 
Updated exclusion criterion 7 (into 3 parts) to add clarity 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 


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Change 
Number 
Change Description 
16 
Updated exclusion criterion 16 (participation in an interventional clinical study with 
30-day wash-out period) 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 
17 
Added exclusion criterion 17 (New requirement to exclude subjects with a newly 
detected unorganized thrombus prior to randomization) 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 
18 
Added exclusion criterion 18 (Hypersensitivity to the active ingredient or to any of the 
excipients of any components of the trial treatment) 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 
19 
Added exclusion criterion 19 (for patients with a history of thrombosis who are 
diagnosed with antiphospholipid syndrome) 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 
20 
Updated relevant time period for subjects who discontinue study treatment for 
primary efficacy objective, a secondary safety objective (comparing edoxaban with 
SOC with respect to all bleedings), and an exploratory analysis 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 2.1.1 Primary Objectives  
 
Section 2.1.2.1 Key Secondary Objectives  
 
Section 2.3.1 Primary Safety Endpoint  
 
Section 2.3.2 Secondary Safety Endpoints 
 
Section 11.4.1.2 Exploratory Efficacy Analysis 
 
Section 11.4.3.1 Analysis of Bleeding Events 


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Change 
Number 
Change Description 
21 
Added body weight criteria to allow dose adjustments in extension phase 
The following sections of the protocol were updated: 
 
Synopsis  
 
Section 5.1.1 Treatment Groups 
 
Section 5.1.1.1 Edoxaban-Treatment Arm (Randomization through Month 12, 
and All SOC Subjects Converted to Edoxaban after Month 3) 
 
Table 5.1 Edoxaban Dose Recommended for 3 Cohorts (12 to <18 years, 6 to 
<12 years, and 2 to <6 years) 
 
Section 5.3.1 Edoxaban Dose Reduction 
22 
Clarified that the Cockcroft-Gault formula applies to determining renal impairment 
in pediatric subjects equal to 12 years of age 
The following sections of the protocol were updated: 
 
Table 5.1 Edoxaban Dose Recommended for 3 Cohorts (12 to <18 years, 6 to 
<12 years, and 2 to <6 years) 
 
Section 5.6.3 Reasons for Discontinuation from Study Treatment 
 
Appendix 17.9 Estimated Glomerular Filtration Rate (eGFR) Assessment 
23 
Clarification on INR testing to initiate SOC post screening 
The following section of the protocol was updated: 
 
Section 5.2.4.3 To Initiate SOC Treatment 


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Change 
Number 
Change Description 
24 
Modified echocardiogram assessments to not specifically require a transthoracic 
echocardiogram 
The following sections of the protocol were updated: 
 
Synopsis 
 
Section 4.2 Exclusion Criteria 
 
Section 6.1 Note Concerning Transthoracic Echocardiogram 
 
Section 6.2 Screening/Qualification Visit (At least Day -30 to 1, Visit 1) 
 
Section 6.4.4 Month 3 (Visit 5; End of Main Treatment Period) Procedures 
 
Section 6.5.3 Month 12/Discontinuation Visit (Visit 8; Appropriate for 
subjects completing Month 12 or treated beyond Month 3 and discontinuing 
study prior to Month 12) 
 
Section 7.1 Assessments for Efficacy Endpoint(s) 
 
Table 7.2 Recommended Diagnostic Imaging Methods 
 
Table 17.1 Schedule of Events 
25 
Updated the required INR range to ≤2.5 for subjects to transition from standard of 
care (SOC) treatment to edoxaban 
The following sections of the protocol were updated: 
 
Section 5.1.1 Treatment Groups 
 
Section 5.1.1.1 Edoxaban-Treatment Arm (Randomization through Month 12, 
and All SOC Subjects Converted to Edoxaban after Month 3) 
26 
Updated reporting requirements for serious adverse events 
The following sections of the protocol were updated: 
 
Section 5.6.3 Reasons for Discontinuation from Study Treatment 
 
Section 9.5 Serious Adverse Events and Adverse Event of Special Interest 
Reporting – Procedure For Investigators  
27 
Added the option and process for the Principal Investigator to schedule a visit for 
subjects who switch from SOC to edoxaban in the extension period. 
The following section of the protocol was updated: 
 
Section 6.5 Extension Period (beyond Month 3 – Month 6, 9, and 12; Visits 6, 
7, and 8) 


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Change 
Number 
Change Description 
28 
Updated re-screening procedures to limit to retesting of laboratory test results related 
to a specific inclusion/exclusion criteria 
The following section of the protocol was updated: 
 
Section 5.6.8 Subject Re-screening Procedures 
29 
Modified the provided dosage forms of enoxaparin SOC treatment 
The following section of the protocol was updated: 
 
Section 5.2.1.2 Standard of Care (Randomization through Month 3) 
30 
Updated list of key study personnel 
The following sections of the protocol were updated: 
 
Section 15.12.1 Sponsor’s Responsible Medical Officer and Clinical Study 
Leader 
 
Section 15.12.2 Sponsor’s Safety Contacts 


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PROTOCOL SYNOPSIS 
EudraCT: 
2017-000475-90 
IND Number 
IND 63,266 
Protocol Number: 
DU176b-C-U313 
Investigational Product: 
Edoxaban (DU-176b) 
Active Ingredient(s)/INN: 
Edoxaban tosylate: N-(5-Chloropyridin-2-yl)-N’-[(1S,2R,4S)-4-
(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-
tetrahydro[1,3]thiazolo[5,4-c]pyridine-
2-carboxamido)cyclohexyl] oxamide mono 
(4-methylbenzenesulfonate) monohydrate 
Study 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. 
Study Phase: 
Phase 3 
Indication Under Investigation: Anticoagulant prophylaxis (either as primary or secondary 
prevention) in pediatric subjects with cardiac disease at risk of 
thromboembolic events (TE). 
Study Objectives: 
Primary Objective 
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) bleedings per International Society on Thrombosis and 
Haemostasis [ISTH] definition1 occurring in the Main Treatment 
Period: from the date of first dose of study drug to Month 3 
Visit, or to the date of last dose of study drug plus 3 days if 
study treatment is discontinued, whichever is earlier.  
Secondary Objectives 
The key secondary objectives are:  
 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, systemic embolic event 
(SEE), myocardial infarction (MI), and 


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asymptomatic intracardiac thrombus identified by 
cardiac imaging occurring from randomization to 
Month 3 Visit. 
 To compare the safety of edoxaban against SOC with 
regard to all bleedings that occur in the Main 
Treatment Period: from the date of first dose of study 
drug to Month 3 Visit, or to the date of last dose of 
study drug plus 3 days if study treatment is 
discontinued, whichever is earlier. 
 To compare the efficacy of edoxaban against SOC 
with regard to death as a result of a TE occurring 
from randomization to Month 3 Visit 
 To compare edoxaban against SOC with regard to 
all-cause mortality from randomization to Month 3 
Visit. 
 To assess the safety of edoxaban with regard to the 
combination of major and CRNM bleedings 
occurring during the Extension Period (from Month 3 
Visit to last dose plus 30 days). 
 To assess the efficacy of edoxaban with regard to the 
development of symptomatic TE or asymptomatic 
intracardiac thrombus identified by cardiac imaging 
occurring during the Extension Period. 
 To assess the safety of edoxaban with regard to all 
bleedings occurring during the Extension Period. 
 To assess the efficacy of edoxaban with regard to 
death as a result of a TE occurring during the 
Extension Period. 
 To assess the efficacy of edoxaban with regard to all-
cause mortality occurring during the Extension 
Period. 
 To evaluate the population pharmacokinetics and 
pharmacodynamics of edoxaban in relation to the 
efficacy and safety endpoints in subjects with cardiac 
conditions at risk of TE. 
Exploratory Objectives 
The exploratory objectives are: 
 To assess the quality of life using validated 
questionnaires. 


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 To compare the intra-patient safety (Investigator 
reported bleeding) and efficacy (Investigator reported 
TE) during the Main Treatment Period compared 
with the prior treatment occurring within 3 months of 
randomization. 
 To compare edoxaban regimen with available 
existing historical data based on literature review and 
search for registered clinical trials with similar 
endpoints. 
 To analyze the primary prevention and secondary 
prevention of TE. 
Study Design: 
This is a Phase 3, open-label, randomized, parallel-group, 
multicenter, observational trial to evaluate safety and efficacy of 
edoxaban against SOC. The adjudication of the efficacy and 
safety endpoints will be conducted by a blinded adjudication 
committee.  
The study includes two periods: 
 The Main Treatment Period is defined as the time 
from randomization, until the end of Month 3 of 
treatment.  
 Subjects who discontinue treatment from the 
Main Treatment Period prior to Month 3 will 
continue to be followed monthly according to the 
Schedule of Events (Table 17.1) through the 
Month 3 visit (Visit 5) and have a 30-day Follow-
Up Visit. If treatment discontinuation occurs 
prior to Month 2 visit, the 30-day Follow-Up 
Visit will occur on the same day as the Month 3 
visit.  
 Subjects who complete the Main Treatment 
Period (Month 3) but do not continue into the 
Extension Period will have a Month 3 Visit and 
with a Follow-Up Visit 30 days after last dose of 
study drug, and discontinued from the study. 
 Subjects who withdraw from the study (meaning 
the subject can no longer participate in the study 
due to withdrawal of consent) will have an 
attempted Follow-Up Visit phone call 3 months 
from date of randomization to ascertain if any 
events (TE and/or bleeding events) have occurred 
since withdrawal. 


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 The Extension Period is discretionary for the subject 
based on the Investigator’s judgment of risk burden 
and will include treatment from the end of the Main 
Treatment Period (Month 3, Visit 5) up through the 
end of Month 12 (Visit 8). All subjects entering the 
Extension Period will be given edoxaban for the 
duration of the Extension Period. 
 All subjects after Month 3 will be provided with 
edoxaban at the dosage appropriate for the subject’s 
age and weight. 
 Subjects who discontinue the treatment and study 
at any time after Month 3 will have a 
Discontinuation Visit performed with a 
subsequent 30-day Follow-Up. 
 Subjects who complete Extension Period 
treatment at Month 12 (Visit 8) will have a 
Follow-Up Visit, 30 days after last dose of study 
drug (Visit 9). 
Subjects who require anticoagulant treatment after 
discontinuation of the study treatment at any time will be 
transitioned to a therapy as determined by the Investigator. After 
subjects are assessed for eligibility to participate in the study per 
the inclusion/exclusion criteria, they will be: 
 Stratified by:  
 Type of underlying heart disease 
 Kawasaki disease 
 Fontan surgery 
 Heart failure  
 Others (which can include post-surgical 
procedures for congenital heart diseases other 
than Fontan surgery) 
 Subjects with underlying disease other than 
Kawasaki will be further stratified by 
concomitant use of low dose aspirin (1 to 
5 mg/kg/day) 
 About 150 subjects will be recruited globally and be 
randomized in a 2:1 ratio (edoxaban:SOC, 
respectively) into 1 of 2 treatment arms: 


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 Edoxaban-treatment arm: subjects will receive a 
selected dose of edoxaban  
Or 
 SOC-treatment arm subjects will receive SOC 
anticoagulant according to clinical site’s SOC 
treatment practice, as follows (alone or in 
combination): 
 Heparin, including unfractionated heparin 
(UFH) or low molecular weight heparin 
(LMWH)  
 Vitamin K antagonist (VKA) with potential 
bridging with heparin based therapy until 
VKA international normalized ratio (INR) is 
in therapeutic range 
Locally sourced SOC is the preferred option for the study. 
However, centrally sourced SOC can be provided when country 
or clinical site requirements deem it necessary. 
Subjects from 1 to <18 years of age will be enrolled in the study 
as soon as the dosing regimen is established for each age cohort 
in the Phase 1 single-dose U157 study. U157 has 5 dosing age 
cohorts which are similar to this study: 
 Ages 12 to <18 years  
 Ages 6 to <12 years  
 Ages 2 to <6 years  
 Ages 6 months to <2 years 
(In Cohort 4 [6 months to <2 years], enrollment 
may open after the protocol data requirement for 
Independent Data Monitoring Committee 
[IDMC] review for subjects less than 1 year old 
[from study U157] is met and the IDMC reviews 
and approves the data. Sites will be notified that 
enrollment of subjects 6 month old to <1 year old 
may also open.) 
 Ages birth to <6 months.  
A review of safety data of 10%, 25%, 50%, and 75% of subjects 
completing the Main Treatment Period of 3 months will be 
performed on a routine basis by the IDMC. In addition, the 
IDMC will review the edoxaban exposure analysis and safety 


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data from each age cohort in the U157 study to approve the 
proposed dose for the same age cohort in U313 study. 
Additionally, in U313, subjects less than 1 year of age will be 
admitted to the study after review by the IDMC of safety data of 
50% of subjects in the 1 to <18 years age group who have 
completed the Main Treatment Period of 3 months (50 subjects 
in edoxaban arm and 25 subjects in SOC arm).  
The older cohort (12 to <18 years of age) will receive tablets (15 
and/or 30 mg strength, see Table 5.1) or be offered granules for 
oral suspension if swallowing is an issue. Subjects 6 to <12 
years of age may take edoxaban tablets or edoxaban granules for 
oral suspension, which will provide more flexibility to adjust 
mg/kg dose. All subjects <6 years old will receive edoxaban 
granules oral suspension (see Table 5.1). Subjects will be 
instructed to take the edoxaban dose orally once a day, at the 
same time every day, preferably in the morning, with or without 
food. One bottle of edoxaban granules will be used for each 
dosing day. Tablets should be swallowed with a glass of water.  
Study Duration: 
The total duration of the study is expected to be approximately 3 
years. 
The total duration of study participation for any individual 
subject will be a minimum of 4 months (3-month Main 
Treatment Period and 30-day Follow-Up) and maximum of 13 
months (3-month Main Treatment Period, 9-month Extension 
Period and 30-day Follow-Up). 
Clinical Sites and Location: 
This study will be conducted in North America, European 
Union, and Rest of the World (ROW).  


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Subject Eligibility Criteria: 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be eligible 
for the study: 
1. Children with cardiac diseases who are at risk for 
thromboembolic complications and require at least 
3 months antithrombotic anticoagulant prophylaxis. 
Either one of the following criteria may apply: 
a. Children with cardiac disease who have a history of 
cardiac shunt occlusion/thrombosis, with shunt still 
in place (secondary prevention). 
OR 
b. Children with cardiac disease who require (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.1 Some examples of cardiac 
conditions at risk of thrombosis are Fontan surgery, heart 
failure, Kawasaki disease, and Blalock-Taussig and 
Glenn surgery.  
2. Male or female children 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. 
3. 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 
with edoxaban treatment. Pediatric subjects 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. 
4. Female subjects of childbearing potential must test 
negative for pregnancy at Randomization and must 
consent to avoid becoming pregnant by using a locally 
approved contraception method throughout the study. 


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For locally approved contraceptive methods, see 
Appendix 17.3.  
5. If the subject has a history of a TE that meets all of the 
following criteria: 
 Old, organized and/or resolved per the discretion of 
the Principal Investigator (confirmation of an old, 
organized and or resolved TE is not required by any 
imaging studies), and 
 The subject is asymptomatic, and 
 The subject continues to require at least 3 months of 
anti-coagulation treatment, and 
 There is no intracardiac thrombus or thrombi on the 
screening echo, and  
 All other inclusion and exclusion criteria are met. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be 
disqualified from entering the study: 
1. Subjects with a history of the following up to 
randomization: 
 Symptomatic venous or arterial TE 
 Asymptomatic venous or arterial TE found by 
routine imaging 
 Asymptomatic intracardiac thrombosis confirmed by 
an echocardiogram during the study screening 
period. 
Note: Valid echocardiograms are images taken 
within 5 weeks prior to Randomization Visit. 
2. Subjects with mechanical heart valves. 
3. Subjects with active bleeding or high risk of bleeding 
contraindicating treatment with anticoagulant. 
4. Subjects with a contraindication to the use of heparin 
(UFH or LMWH) and/or VKA (see Appendix 17.4). 
5. Co-administration of antithrombotic therapy is 
contraindicated in edoxaban arm and SOC arm except 
for low dose aspirin defined as 1 to 5 mg/kg/day with 
maximum of 100 mg/day (see Appendix 17.5). 


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6. Administration of rifampin is prohibited during the study 
and subjects on concomitant use of rifampin are 
excluded Appendix 17.5.6. 
7. a) Subjects with severe hepatic impairment or hepatic 
disease associated with coagulopathy (eg, acute hepatitis, 
chronic active hepatitis, and cirrhosis).                               
b) Subjects with ALT >5 × the upper limit of normal 
(ULN) or total bilirubin >2 × ULN with direct bilirubin 
>20% of the total at Screening.     
c) Subjects with aPTT >50 seconds or international 
normalized ratio [INR] >2.0 not related to 
anticoagulation therapy at Screening. 
8. Subjects with estimated glomerular filtration rate (eGFR) 
<30% of normal for age and size (see Appendix 17.9) 
9. Subjects with stage 2 hypertension defined as blood 
pressure systolic and/or diastolic confirmed >99th 
percentile plus 5 mmHg (see Appendix 17.10). 
10. Subjects with thrombocytopenia (thrombocytes <50 × 
109/L). 
11. Subjects with Fontan procedure with a history of or 
signs/symptoms suggestive of protein-losing 
enteropathy. 
12. Subjects with a life expectancy less than the expected 
study duration (3 months). 
13. Subjects who are known to be pregnant or breastfeeding. 
14. Subjects who are not using an approved method of 
contraception (see Appendix 17.3). 
15. 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 identified in Appendix 17.5. 
16. Subject who participated in another interventional 
clinical study or treated with an experimental therapy 
with less than a 30-day wash-out period prior to 
Screening Visit. 
17. If any imaging is performed prior to randomization and 
results show a newly detected unorganized thrombus, 
these subjects are NOT eligible for the study. 


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18. Hypersensitivity to the active ingredient or to any of the 
excipients of any components of the trial treatment. 
19. Patients with a history of thrombosis who are diagnosed 
with antiphospholipid syndrome who are triple positive 
(for lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies. 
Dosage Form, Dose and Route 
of Administration: 
Randomization to Edoxaban-Treatment Arm 
Edoxaban treatment will be packaged and dispensed to the 
subject on a monthly schedule, even though after Month 3 the 
clinic visitation schedule is every 3 months. For subjects who 
cannot pick up their study therapy on a monthly basis, 
accommodations will be made to allow the Investigator to 
distribute up to a 3-month supply of study drug to match the 
scheduled study visit interval.  
The following dosage forms will be provided for this study: 
 Edoxaban 15 mg and 30 mg tablets 
 Edoxaban granules for oral suspension 60 mg are 
provided in individual bottles. Granules will be 
reconstituted in 8 mL water to provide a 6 mg/mL 
liquid suspension). One bottle will be used for each 
daily dose. 
For subjects 12 to <18 years old; 
 60 mg dose will be dispensed as two 30 mg tablets or 
as 10 mL from an individual bottle of oral suspension 
60 mg 
 45 mg dose will be dispensed as one 30 mg tablet 
plus one 15 mg tablet or as 7.5 mL from an 
individual bottle of oral suspension 60 mg 
 30 mg dose will be dispensed as one 30 mg tablet or 
as 5 mL from an individual bottle of oral suspension 
60 mg  
 Doses provided by the granulation formulation will 
be dispensed with a dosing syringe according to the 
recommended dose shown in Table 5.1. One bottle 
will be used for each daily dose. 
 If a subject does not have the capacity to swallow 
tablets in the 12 to <18 year old or 6 to <12 year old 
group, the tablets may be crushed and served with 
applesauce or mixed with 2 to 3 ounces of water and 


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immediately administered by mouth or through an 
existing gastric tube, if needed. 
For subjects 6 to <12 years old; 
 60 mg dose will be dispensed as two 30 mg tablets or 
as 10 mL from an individual bottle of oral suspension 
60 mg. 
 45 mg dose will be dispensed as one 30 mg tablet 
plus one 15 mg tablet or as 7.5 mL from an 
individual bottle of oral suspension 60 mg. 
 Dose other than 45mg and 60mg provided by the 
granulation formulation will be dispensed with a 
dosing syringe according to the recommended dose 
shown in Table 5.1. One bottle will be used for each 
daily dose. 
Subjects younger than 6 years of age will only receive edoxaban 
granules for oral suspension, which will give more flexibility to 
adjust mg/kg dose. Doses for all age groups will be selected to 
elicit target exposures comparable to those achieved from the 
adult Phase 3 study of 60 mg. Table 5.1 indicates the edoxaban 
doses to be given for subjects of the ages 2 to <18 years of age. 
Doses for all subsequent age cohorts will be by separate 
notification to the investigative sites outside the content of this 
protocol after the IDMC has approved the proposed edoxaban 
doses and safety data from the U157 study. 
Pediatric dosing regimen will be determined from Phase 1 
single-dose U157 study. 
Additionally, there is ongoing review of safety data of 10%, 
25%, 50%, and 75% of subjects completing Month 3 of the 
study by the IDMC in the U313 study. 
Subjects will be instructed to take edoxaban (tablets or granules) 
orally once a day, at the same time every day, preferably in the 
morning, with or without food. Tablets should be swallowed 
with a glass of water. Doses provided from the granulation 
formulation will be provided by a dosing syringe. One bottle 
will be used for each daily dose. 
Edoxaban dosage regimen will be reduced (see Section 5.3.1) 
for the following reasons. Refer to Table 5.1 for dosing 
instruction for subjects of age 2 to <18 years of age: 
 Body Weight:  


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 For subjects 12 to <18 years old  with body 
weight <5th percentile of subject’s age (see 
Appendix 17.11 ), edoxaban doses will be 
permanently changed 
 For subjects 12 to <18 years old  with body 
weight ≥60 kg, will receive edoxaban 60 mg. 
However, if the body weight is ≥30 - <60 kg, 
edoxaban dose would be 45 mg daily. If the 
patient body weight ≥60 kg, then edoxaban dose 
would be escalated to 60 mg daily. 
 For subjects <12 year olds: Doses will be 
provided by mg/kg or a dose may be suggested, 
subsequent to exposure modeling, based on an 
age range (see Table 5.1). 
 Moderate renal impairment (eGFR) ≥30% to ≤50% 
of normal for the subject’s age and size at 
randomization as determined by the age appropriate 
formula: Cockcroft-Gault equation for pediatric 
subjects ≥12 years of age and modified Schwartz 
equation for pediatric subjects <12 years of age) 
(Appendix 17.9). If a subject experiences a change in 
renal function from normal to eGFR ≥30% to ≤50% 
after randomization, the measurement will be 
repeated within 1 week. If the repeat measurement 
confirms the decrease, the edoxaban dose will be 
reduced permanently. 
 Additionally, if a subject requires concomitant 
administration of a certain P-glycoprotein (P-gp) 
inhibitor (Appendix 17.6.1 ), the edoxaban dose will 
be reduced during P-gp administration and re-
established to the original dose once P-gp inhibitor 
administration had concluded. 
Randomization to Standard of Care Treatment Arm 
SOC randomized subjects will be treated with SOC though 
Month 3 (Visit 5) then offered edoxaban through Month 12 
(Visit 8). SOC treatment will be packaged and dispensed to the 
subject on a monthly visit schedule. After Month 3, all subjects 
will be transitioned to edoxaban at the appropriate dose for their 
age and weight.  
Local Sourcing of SOC: 


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Local SOC sourcing is the primary method for providing 
heparin and/or VKA: 
The SOC will be provided by the Investigator. Alternatively, 
local supply depots within each country will provide SOC 
directly to the clinical sites. Subject will be treated with heparin 
(UFH or LMWH), and/or VKA according to the clinical site’s 
SOC treatment regimen (see Section 5.2). 
Note: If standard practice for bridging VKA to therapeutic levels 
is achieved with a heparin based treatment, the clinical site will 
be responsible for providing the bridging therapy to subjects 
randomized to VKA. 
Central/Sponsor Sourcing: 
If there are regulatory or site hurdles providing the SOC locally, 
the Sponsor will provide SOC only as LMWH (enoxaparin) or 
VKA (warfarin) as follows:  
 Enoxaparin  Subjects will be treated with 
enoxaparin alone or can be switched to warfarin 
anytime during the study treatment period. 
 Enoxaparin (LMWH) will be provided as 
solution for subcutaneous injection in pre-filled 
syringes with only 60 mg/0.6 mL, 80 mg/0.8 mL, 
or 100 mg/1 mL concentration for injection, or as 
multiple dose vials (for subjects <20 kg) for 
injection. 
 Warfarin (VKA) will be supplied as tablets (0.5 mg, 
1 mg, and 3 mg). 
Note: Clinical sites or treating physicians will provide aspirin 
(as per local SOC practice). 
Study Endpoints: 
All safety and efficacy endpoints described will be adjudicated 
in a blinded manner by the Clinical Events Committee (CEC). 
An Independent Data Monitoring Committee (IDMC) will 
monitor safety throughout the duration of the study. 
Primary Safety Endpoint 
The primary safety endpoint is a combination of major bleeding 
events and CRNM bleeding events per ISTH definition 
occurring during the Main Treatment Period: from the date of 
first dose of study drug to Month 3 Visit, or to the date of last 
dose of study drug plus 3 days if study treatment is 
discontinued, whichever is earlier. 


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Secondary Safety Endpoints 
The secondary safety endpoints are: 
 All bleeding events occurring during the Main 
Treatment Period, from the date of first dose of study 
drug to Month 3 Visit, or to the date of last dose of 
study drug plus 3 days if study treatment is 
discontinued, whichever is earlier. 
 A combination of major and CRNM bleedings from 
the day after Month 3 Visit to the date of the last 
dose of study medication plus 30 days for subjects 
who participate in the Extension Period. 
 All bleeding events from the day after the Month 3 
Visit to the date of last dose of study medication plus 
30 days for subjects who participate in the Extension 
Period. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 The combination of symptomatic TE in the systemic 
arterial or venous pathways including DVT, PE, 
stroke, intracardiac thrombus, SEE, and MI, and 
asymptomatic intracardiac thrombus identified by 
cardiac imaging, that occur from randomization to 
Month 3 Visit.  
 Deaths as a result of TE that occurs from 
randomization to Month 3 Visit. 
 All-cause mortality from randomization to Month 3 
Visit. 
 The combination of symptomatic TE in the systemic 
arterial or venous pathways and asymptomatic 
intracardiac thrombus identified by cardiac imaging, 
that occur from the day after the Month 3 Visit to the 
date of the last dose of study drug plus 30 days for 
subjects who participate in the Extension Period.  
 Deaths as a result of TE that occurs from the day 
after Month 3 Visit to the date of the last dose of 
study drug plus 30 days for subjects who participate 
in the Extension Period. 
Pharmacokinetic (PK)/Pharmacodynamic (PD)/Biomarker 
Endpoint(s) 


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Plasma concentrations of edoxaban and its metabolite, D21-
2393, will be assessed in subjects who receive at least 1 dose of 
edoxaban treatment and have measurable concentrations of 
edoxaban and/or D21-2393. Population PK analysis will be 
conducted to characterize the PK profiles of edoxaban in this 
target subject population.  
The PD biomarkers of coagulation, PT, aPTT, and anti-activated 
Factor X (FXa) will be assessed as secondary endpoints in 
edoxaban-treated subjects. 
Other biomarkers may be tested related to coagulation and/or 
edoxaban’s mechanism of action. 
Planned Sample Size: 
The total number of subjects planned is 150 subjects. Of these, 
100 subjects will be treated with edoxaban and 50 subjects will 
be given SOC.  
Statistical Analyses: 
Analysis Sets: 
Randomized Analysis Set will include all subjects who sign the 
informed consent form and are randomized. 
Safety Analysis Set will include all subjects in the Randomized 
Analysis Set who received at least 1 dose of study drug. 
Analysis will be based on the study drug the subject actually 
received. 
Modified intention-to-treat Analysis Set will include all subjects 
in the Randomized Analysis Set who received at least 1 dose of 
study drug. Analysis will be based on the study drug the subject 
was randomized to receive. 
PK Analysis Set will include all subjects in the Safety Analysis 
Set who had at least 1 PK sample with measurable 
concentration.  
PD Analysis Set will include all subjects in the Safety Analysis 
Set who had at least 1 measurable PD sample. 
Safety Analyses: 
Analysis of Primary Safety Endpoint 
A descriptive statistical analysis will be performed for the 
primary safety endpoint, ie, the composite of major and CRNM 
bleeding events that occur during the Main Treatment Period: 
from the date of first dose of study drug to the Month 3 Visit, or 
to the date of last dose of study drug plus 3 days if study 
treatment is discontinued, whichever is earlier. This analysis will 
be based on CEC adjudication results. 


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The time to major or CRNM bleeding occurring during the Main 
Treatment Period will be compared between treatment groups 
for subjects in the Safety Analysis Set, using the Cox 
proportional hazards regression model including treatment 
group, concomitant usage of aspirin, and underlying disease 
(Kawasaki disease, Fontan surgery, Heart Failure or Other) as 
covariates. Hazard ratio between edoxaban and SOC treatment 
group will be calculated with corresponding 95% confidence 
interval. The incidence, annualized event rate, and rate 
difference between edoxaban and SOC treatment groups will 
also be calculated.  
Analysis of Secondary Safety and Efficacy Endpoints: 
The incidence, annualized event rate, and rate difference 
between edoxaban and SOC treatment groups of other secondary 
safety and efficacy endpoints for the Main Treatment Period will 
be summarized by treatment group. 
The incidence and annualized event rate of other secondary 
safety and efficacy endpoints for the Extension Period will be 
summarized for the edoxaban treatment group. 
Exploratory Analysis:  
Quality of life will be assessed using validated questionnaires.  
Intra-patient safety (Investigator-reported bleeding) and efficacy 
(Investigator-reported TE) during the Main Treatment Period 
will be compared with the previous 3-month pre-randomization 
period of anticoagulant regimen.  
The incidence and event rate of safety and efficacy endpoint in 
the Main Treatment Period will be summarized for comparing 
edoxaban regimen with available existing historical control data 
based on literature review and search for registered clinical trials 
with similar endpoints.   
A separate sub-analysis of primary prevention and secondary 
prevention events will be provided if data allow. TE will be 
classified as primary prevention and secondary prevention 
events and summarized by treatment group for events occurring 
during the Main Treatment Period. 
Interim Assessment: 
There is no formal statistical interim analysis planned. However, 
an interim assessment by the IDMC of safety endpoints of the 
study will take place after the first 50 subjects in the edoxaban 
treatment group and 25 subjects in the SOC arm from 1 to <18 


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years of age complete the first 3 months of treatment. This will 
allow for enrollment of subjects <1 year of age.  
PK and PD Analysis (Edoxaban Subjects Only):  
Plasma concentration and biomarker data will be summarized by 
age, dose and time point using descriptive statistics. The plasma 
concentration data will be pooled with data from other studies 
for a population PK analysis using nonlinear mixed effects 
modeling.  
Exposure-response relationships will be evaluated for the safety 
and efficacy endpoints through a model based approach, if data 
allow.  
 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
GLOBAL AMENDMENT, PROTOCOL VERSION 4.0 ...............................................................3 
PROTOCOL SYNOPSIS ..............................................................................................................10 
TABLE OF CONTENTS ...............................................................................................................27 
LIST OF TABLES .........................................................................................................................34 
LIST OF FIGURES .......................................................................................................................35 
LIST OF ABBREVIATIONS ........................................................................................................36 
1. 
INTRODUCTION ........................................................................................................39 
1.1. 
Background ...................................................................................................................39 
1.2. 
Study Rationale .............................................................................................................39 
1.3. 
Risk/Benefit ..................................................................................................................40 
2. 
STUDY OBJECTIVES, HYPOTHESIS AND ENDPOINTS......................................43 
2.1. 
Study Objectives ...........................................................................................................43 
2.1.1. 
Primary Objectives ........................................................................................................43 
2.1.2. 
Secondary Objectives ....................................................................................................43 
2.1.2.1. 
Key Secondary Objectives ............................................................................................43 
2.1.2.2. 
Other Secondary Objectives ..........................................................................................44 
2.1.3. 
Exploratory Objectives..................................................................................................44 
2.2. 
Study Hypothesis ..........................................................................................................44 
2.3. 
Study Endpoints ............................................................................................................44 
2.3.1. 
Primary Safety Endpoint ...............................................................................................44 
2.3.2. 
Secondary Safety Endpoint(s) .......................................................................................44 
2.3.3. 
Secondary Efficacy Endpoints ......................................................................................45 
2.3.4. 
Pharmacokinetic (PK)/Pharmacodynamic (PD)/Biomarker Endpoint(s) .....................45 
2.3.5. 
Quality of Life Assessment ...........................................................................................45 
3. 
STUDY DESIGN ..........................................................................................................47 
3.1. 
Overall Design ..............................................................................................................47 
3.2. 
Discussion of Study Design ..........................................................................................47 
3.3. 
End of Study ..................................................................................................................49 
4. 
STUDY POPULATION ...............................................................................................50 
4.1. 
Inclusion Criteria ...........................................................................................................50 


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4.2. 
Exclusion Criteria..........................................................................................................51 
4.3. 
Additional Requirements ..............................................................................................52 
4.3.1. 
Stopping Rules for Study: .............................................................................................52 
5. 
STUDY TREATMENT(S) ...........................................................................................53 
5.1. 
Assigning Subjects to Treatments and Blinding ...........................................................53 
5.1.1. 
Treatment Groups..........................................................................................................53 
5.1.1.1. 
Edoxaban-Treatment Arm (Randomization through Month 12, and All SOC 
Subjects Converted to Edoxaban after Month 3) ..........................................................54 
5.1.1.2. 
Standard of Care Treatment Arm (Randomization to Month 3). ..................................56 
5.1.2. 
Method of Treatment Allocation ...................................................................................56 
5.1.3. 
Blinding .........................................................................................................................57 
5.1.4. 
Emergency Unblinding Procedure ................................................................................57 
5.2. 
Study Drug(s) ................................................................................................................57 
5.2.1. 
Description ....................................................................................................................57 
5.2.1.1. 
Edoxaban (Randomization through Month 12).............................................................57 
5.2.1.2. 
Standard of Care (Randomization through Month 3) ...................................................58 
5.2.1.3. 
Aspirin ...........................................................................................................................59 
5.2.2. 
Labeling and Packaging ................................................................................................59 
5.2.2.1. 
Edoxaban .......................................................................................................................59 
5.2.2.2. 
Standard of Care ............................................................................................................59 
5.2.3. 
Preparation ....................................................................................................................59 
5.2.3.1. 
Edoxaban .......................................................................................................................59 
5.2.3.2. 
Standard of Care ............................................................................................................59 
5.2.4. 
Administration ..............................................................................................................60 
5.2.4.1. 
To Initiate Edoxaban Treatment at Randomization ......................................................60 
5.2.4.2  
Transition SOC-Treated Subjects during the Main Treatment Period to 
Edoxaban in the Extension Period ................................................................................60 
5.2.4.3  
To Initiate SOC Treatment ............................................................................................61 
5.2.5. 
Storage...........................................................................................................................62 
5.2.6. 
Drug Accountability ......................................................................................................62 
5.2.6.1. 
Edoxaban .......................................................................................................................62 
5.2.6.2. 
Standard of Care ............................................................................................................63 
5.3. 
Dose Interruptions and Reductions ...............................................................................64 


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5.3.1. 
Edoxaban Dose Reduction ............................................................................................64 
5.4. 
Method of Assessing Treatment Compliance ...............................................................65 
5.5. 
Prior and Concomitant Medications..............................................................................65 
5.6. 
Subject Withdrawal/Discontinuation ............................................................................66 
5.6.1. 
Discontinuation from Treatment within the Main Treatment Period (Month 3) ..........66 
5.6.2. 
Discontinuation from Treatment and Study beyond Month 3 up to Month 12 .............66 
5.6.3. 
Reasons for Discontinuation from Study Treatment .....................................................66 
5.6.4. 
Reasons for Withdrawal at any Time during the Study ................................................68 
5.6.5. 
Withdrawal Procedures .................................................................................................68 
5.6.6. 
Procedures for Discontinuation from Treatment or Study; or Withdrawal from 
Study .............................................................................................................................69 
5.6.7. 
Follow-Up Procedures. .................................................................................................70 
5.6.7.1. 
Temporary Interruption of Study Drug .........................................................................70 
5.6.8. 
Subject Re-screening Procedures ..................................................................................70 
6. 
STUDY PROCEDURES ..............................................................................................71 
6.1. 
Note Concerning Echocardiogram ................................................................................71 
6.2. 
Screening/Qualification Visit (At Least Day -30 to Day 1, Visit 1) .............................72 
6.3. 
Randomization (Day 1, Visit 2) ....................................................................................73 
6.4. 
Main Treatment Period .................................................................................................75 
6.4.1. 
Subjects Randomized to the Edoxaban-Treatment Arm: ..............................................75 
6.4.2. 
Subjects Randomized to the SOC-Treatment Arm: ......................................................75 
6.4.3. 
Monthly Visits (Months 1 and 2; Visits 3 and 4) for both arms: ..................................75 
6.4.3.1. 
Month 1 Visit (Visit 3) Procedures ...............................................................................76 
6.4.3.2. 
Month 2 (Visit 4) Procedures ........................................................................................76 
6.4.4. 
Month 3 (Visit 5; End of Main Treatment Period) Procedures .....................................77 
6.5. 
Extension Period (beyond Month 3  Month 6, 9, and 12; Visits 6, 7, and 8)..............78 
6.5.1. 
Month 6 (Visit 6) Procedures ........................................................................................79 
6.5.2. 
Month 9 (Visit 7) Procedures ........................................................................................79 
6.5.3. 
Month 12/Discontinuation Visit (Visit 8; Appropriate for subjects completing 
Month 12 or treated beyond Month 3 and discontinuing study prior to Month 
12) .................................................................................................................................80 
6.6. 
Required 30-Day Follow-Up Visit (Visit 9) .................................................................80 


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6.7. 
Required Month 3 Follow-Up Phone Call for Withdrawal Subject Prior to 
Month 3. ........................................................................................................................81 
7. 
EFFICACY ASSESSMENTS .......................................................................................82 
7.1. 
Assessments for Efficacy Endpoint(s) ..........................................................................82 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) ...................................................88 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................89 
8.1. 
Pharmacokinetic (PK) Assessment(s) ...........................................................................89 
8.2. 
Pharmacodynamic (PD) Assessment(s) ........................................................................89 
8.3. 
Biomarker Assessment(s)..............................................................................................89 
8.4. 
Immunogenicity ............................................................................................................89 
8.5. 
Pharmacogenomic Analysis ..........................................................................................90 
9. 
SAFETY EVALUATION AND REPORTING ...........................................................91 
9.1. 
Assessment of Safety Endpoint(s) ................................................................................91 
9.2. 
Adverse Event Collection and Reporting ......................................................................93 
9.3. 
Adverse Events of Special Interest ...............................................................................95 
9.3.1. 
Liver Enzyme Abnormalities/Liver Dysfunction..........................................................95 
9.4. 
Adverse Event ...............................................................................................................96 
9.4.1. 
Definition of Adverse Event .........................................................................................96 
9.4.2. 
Serious Adverse Event ..................................................................................................96 
9.4.3. 
Severity Assessment .....................................................................................................97 
9.4.4. 
Causality Assessment ....................................................................................................97 
9.4.5. 
Action Taken Regarding Study Drug(s) .......................................................................97 
9.4.6. 
Other Action Taken for Event .......................................................................................98 
9.4.7. 
Adverse Event Outcome ...............................................................................................98 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest Reporting  
Procedure For Investigators ..........................................................................................98 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................99 
9.7. 
Exposure In Utero During Clinical Studies ................................................................100 
9.8. 
Clinical Laboratory Evaluations .................................................................................100 
9.8.1. 
Hematology .................................................................................................................100 
9.8.2. 
Blood Chemistry .........................................................................................................101 
9.8.3. 
Liver Function Test .....................................................................................................101 


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9.8.4. 
Estimated Glomerular Filtration Rate (eGFR) Assessment ........................................101 
9.8.5. 
Urinalysis ....................................................................................................................101 
9.8.6. 
Hepatitis Serology .......................................................................................................102 
9.8.7. 
Urine Pregnancy Testing .............................................................................................102 
9.9. 
Physical Examination ..................................................................................................102 
9.10. 
Electrocardiograms .....................................................................................................103 
9.11. 
Other Examinations .....................................................................................................103 
10. 
OTHER ASSESSMENTS ...........................................................................................104 
11. 
STATISTICAL METHODS .......................................................................................105 
11.1. 
General Statistical Considerations ..............................................................................105 
11.2. 
Analysis Sets ...............................................................................................................105 
11.3. 
Study Population Data ................................................................................................106 
11.4. 
Statistical Analysis ......................................................................................................106 
11.4.1. 
Efficacy Analysis ........................................................................................................106 
11.4.1.1. Secondary Efficacy Analysis ......................................................................................106 
11.4.1.2. Exploratory Efficacy Analysis ....................................................................................107 
11.4.2. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses (Edoxaban Subjects 
Only) ...........................................................................................................................108 
11.4.3. 
Safety Analysis ...........................................................................................................108 
11.4.3.1. Analysis of Bleeding Events .......................................................................................108 
11.4.3.2. Analysis of Hepatic Events .........................................................................................109 
11.4.3.3. Adverse Event Analyses .............................................................................................109 
11.4.3.4. Clinical Laboratory Evaluation Analyses ...................................................................109 
11.4.3.5. Vital Sign Analyses .....................................................................................................110 
11.4.4. 
Other Endpoint Analysis .............................................................................................110 
11.5. 
Interim Assessment .....................................................................................................110 
11.6. 
Sample Size Determination .........................................................................................110 
11.7. 
Statistical Analysis Process .........................................................................................110 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ..............................................112 
12.1. 
Monitoring and Inspections ........................................................................................112 
12.2. 
Data Collection............................................................................................................112 
12.3. 
Data Management .......................................................................................................113 
12.4. 
Study Documentation and Storage ..............................................................................113 


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12.5. 
Record Keeping ...........................................................................................................114 
13. 
FINANCING AND INSURANCE .............................................................................115 
13.1. 
Finances.......................................................................................................................115 
13.2. 
Reimbursement, Indemnity, and Insurance .................................................................115 
14. 
PUBLICATION POLICY ...........................................................................................116 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ..............................117 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance......................................117 
15.2. 
Subject Confidentiality................................................................................................117 
15.3. 
Informed Consent ........................................................................................................117 
15.4. 
Regulatory Compliance ...............................................................................................118 
15.5. 
Protocol Deviations .....................................................................................................119 
15.6. 
Supply of New Information Affecting the Conduct of the Study ...............................119 
15.7. 
Protocol Amendments .................................................................................................120 
15.8. 
Study Termination .......................................................................................................120 
15.9. 
Independent Data Monitoring Committee ..................................................................120 
15.10. 
Clinical Events Committee .........................................................................................121 
15.11. 
Steering Committee/Executive Committee .................................................................121 
15.12. 
Address List ................................................................................................................121 
15.12.1. Sponsor’s Responsible Medical Officer and Clinical Study Leader ...........................122 
15.12.2. Sponsor’s Safety Contacts ..........................................................................................122 
15.12.3. CROs ...........................................................................................................................122 
15.12.4. EDC Partner ................................................................................................................122 
15.12.5. IXRS Partner ...............................................................................................................122 
15.12.6. Central Laboratory Partner ..........................................................................................123 
15.12.7. PD Biomarkers ............................................................................................................123 
15.12.9 
PK Samples All Countries ..........................................................................................123 
15.12.10 Sponsor’s Biostatistician .............................................................................................123 
15.12.11 Drug Labeling, Packaging and Distribution ...............................................................123 
16. 
REFERENCES ............................................................................................................124 
17. 
APPENDICES ............................................................................................................125 
17.1. 
Schedule of Events ......................................................................................................125 
17.2. 
Recommendations per CHEST 2012 Guidelines11 .....................................................130 


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17.3. 
Effective Methods of Birth Control ............................................................................131 
17.4. 
Contraindications for Standard of Care Therapy ........................................................132 
17.5. 
Prohibited Concomitant Medications at Any Time during the Treatment 
Period with Edoxaban or SOC ....................................................................................133 
17.5.1. 
Antiplatelet Drugs .......................................................................................................133 
17.5.2. 
Oral Anticoagulants Other than Study Drug ...............................................................133 
17.5.3. 
Parenteral Anticoagulants ...........................................................................................134 
17.5.4. 
Intravenous Fibrinolytics ............................................................................................134 
17.5.5. 
Non-Steroidal Anti-Inflammatory Drugs (excluding aspirin).....................................134 
17.5.6. 
P-gp Inducers (Prohibited Medication) .......................................................................135 
17.6. 
Concomitant Medications that Require Edoxaban Dose Adjustment .........................136 
17.6.1. 
P-gp Inhibitors List .....................................................................................................136 
17.7. 
Transition From Edoxaban to Other Anticoagulants ..................................................137 
17.8. 
Management of Serious/Life-Threatening Bleeding ...................................................138 
17.9. 
Estimated Glomerular Filtration Rate (eGFR) Assessment ........................................140 
17.10. 
Blood Pressure Levels for Boys and Girls by Age and Height ...................................141 
17.11. 
Growth Chart (2 to 20 years and Birth to 24 Months) ................................................145 
 


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LIST OF TABLES 
Table 5.1: Edoxaban Dose Recommended for 3 Cohorts (12 to <18 years, 6 to <12 
years, and 2 to <6 years) .............................................................................................55 
Table 5.2: Classification of Discontinuation and Withdrawal Status for Subjects by 
Scheduled Visit ...........................................................................................................69 
Table 7.1: Symptoms of Thrombotic Disorders ..........................................................................83 
Table 7.2: Recommended Diagnostic Imaging Methods .............................................................86 
Table 9.1: Hematology Analyses ...............................................................................................101 
Table 9.2: Serum Chemistry ......................................................................................................101 
Table 9.3: Urinalysis Determinations ........................................................................................102 
Table 17.1: Schedule of Events ...................................................................................................126 
Table 17.2: Doses of LMWH (enoxaparin) Used in Pediatric Subjects ......................................130 
Table 17.3: Protocol for Anticoagulation Therapy to Maintain an INR Between 2 and 3 
for Pediatric Subjects (Warfarin Treatment) ............................................................130 
Table 17.4: Thorough List of NSAIDs ........................................................................................135 
Table 17.5: P-gp Inhibitors List ...................................................................................................136 
Table 17.6: Dose Adjustments for INR Elevation .......................................................................139 
Table 17.7: Estimated Glomerular Filtration Rate Based on Age ...............................................140 
 


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LIST OF FIGURES 
Figure 3.1: DU176b-C-U313 Overall Study Design .....................................................................47 
Figure 17.1: Blood Pressure Levels for Boys by Age and Height Percentile ...........................141 
Figure 17.2: Blood Pressure Levels for Girls by Age and Height Percentile ...........................143 
Figure 17.3: Growth Chart (Boys 2 to 20 Years of Age) ..........................................................145 
Figure 17.4: Growth Chart (Girls 2 to 20 Years of Age) ..........................................................146 
Figure 17.5: Growth Chart (Boys Birth to 24 Months of Age) .................................................147 
Figure 17.6: Growth Chart (Girls Birth to 24 Months of Age) .................................................148 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANA 
antinuclear antibody 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
ATE 
arterial thromboembolism 
BMI 
body mass index 
BP 
blood pressure 
CEC 
Clinical Events Committee  
CFR 
Code of Federal Regulations 
CHD 
congenital heart disease 
CI 
confidence interval 
CMV 
cytomegalovirus 
CRF 
case report form 
CRNM 
clinically relevant non-major 
CRO 
Contract Research Organization 
CT 
computed tomography 
CVL 
central venous line 
DVT 
deep vein thrombosis 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EIU 
exposure in utero 
FXa 
activated Factor X 
GCP 
Good Clinical Practice  
ICF 
informed consent form 


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ABBREVIATION 
DEFINITION 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee  
INN 
international non-proprietary name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
IV 
intravenous 
IXRS 
Interactive Web/Voice Response System 
LFT 
liver function test 
LMWH 
low molecular weight heparin 
LOA 
List of Abbreviations 
MI 
myocardial infarction 
mITT 
modified intention-to-treat  
MRI  
magnetic resonance imaging 
MRV 
magnetic resonance imaging with venography 
NSAID 
non-steroidal anti-inflammatory drug 
NVAF 
nonvalvular atrial fibrillation 
PCC 
prothrombin complex concentrate 
PD 
pharmacodynamic 
PE 
pulmonary embolism 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PT 
prothrombin time 
QD 
once a day 
QOL 
quality of life 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 


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ABBREVIATION 
DEFINITION 
SEE 
systemic embolic event 
SOC 
standard of care 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
TE 
thromboembolic event 
TEAE 
treatment-emergent adverse event 
UFH 
unfractionated heparin 
ULN 
upper limit of normal 
US 
ultrasonography 
VKA 
vitamin K antagonist 
VTE 
venous thromboembolism 
WBC 
white blood cell 


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1. 
INTRODUCTION 
1.1. 
Background 
Children with cardiac diseases, including cardiomyopathy and congenital heart disease (CHD) 
constitute a major proportion of children seen in tertiary hospitals with thromboembolic disease. 
In addition, more than 80% of the children receiving primary anticoagulant prophylaxis are being 
treated for complex CHD or severe acquired cardiac illnesses. 
In children with cardiac disease, thromboembolic disease develops as a result of altered 
hemodynamics, prosthetic materials, surgically damaged blood vessels, intravenous (IV) 
catheters, and cardiopulmonary bypass. To prevent this potential life-threatening complication, 
some categories of pediatric cardiac patients, including patients with Fontan circulation, severe 
cardiomyopathy, and mechanic heart valve prostheses, are treated with vitamin K antagonists 
(VKAs) or heparin. 
Many children with CHD require long-term thromboprophylaxis to decrease the morbidity and 
mortality secondary to the thromboembolic phenomenon. The advances in medical and cardio-
surgical techniques have led to improved survival in children with CHD; thus, the overall use of 
anticoagulation has increased. The overall incidence of thrombotic complications in patients 
undergoing cardiac surgery for CHD remains difficult to evaluate due to a lack of data. Giglia et 
al2 showed an incidence of clinically evident TE of 3.6% of 1930 total cardiac operations 
performed. More recently, Manlhiot et al3 revealed that 11% of cardiac operations over a 39-
month period were complicated by TEs. 
1.2. 
Study Rationale 
Currently available anticoagulants have significant limitations especially in the pediatric 
population. At the moment, the commonly used agents for long-term anticoagulation in children 
are low molecular weight heparin (LMWH) and VKAs. The important disadvantages of LMWH 
(such as enoxaparin) are subcutaneous (SC) administration, thrombocytopenia, and therapeutic 
level management. Vitamin K antagonists (such as the coumarins: warfarin, acenocoumarol, or 
phenprocoumon) are indirect coagulation inhibitors, which act by blocking the vitamin K 
dependent liver synthesis of the plasma coagulation factors II, VII, IX, and X. These agents have 
been the only oral anticoagulants available for the last 50 years. The use of VKAs is complicated 
by several inherent problems including a delayed onset of antithrombotic action, a narrow 
therapeutic index that requires close laboratory monitoring using the international normalized 
ratio (INR), an unpredictable and variable pharmacological response, and food and drug 
interactions requiring frequent dosage adjustment. Monagle et al showed that 41% of all warfarin 
measurements were below the target range, which is not uncommon in children taking warfarin4. 
Therefore, there exists a need for a safe, effective, and more easily managed oral antithrombotic 
agent for the treatment of pediatric subjects with thromboembolic disease. 
Edoxaban is an oral direct inhibitor of activated Factor X with predictable pharmacokinetics and 
pharmacodynamics. As a result, anticoagulant effects are more likely to remain within the 
therapeutic range, thereby decreasing the likelihood of bleeding, and potentially removing the 
need for dose adjustment or frequent monitoring. These advantages may result in increased 
patient satisfaction and adherence compared with existing anticoagulants.  


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In 2015, edoxaban was approved for the following indications in the United States:  
 To reduce the risk of stroke and systemic embolism in subjects with nonvalvular 
atrial fibrillation (NVAF) with limitation of use in patients with creatinine clearance 
(CrCl) >95 mL/min.  
 Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 
to 10 days of initial therapy with a parenteral anticoagulant. 
In the European Economic Area and Japan, edoxaban was approved in 2015 for the following 
indications: 
 Prevention of stroke and systemic embolism in adult subjects with NVAF with one or 
more risk factors, such as congestive heart failure, hypertension, age ≥75 years, 
diabetes mellitus, prior stroke or transient ischemic attack with no limitation of use. 
 Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults. 
As of 21 Oct 2018, edoxaban is authorised in 45 countries and is marketed in 30 countries 
worldwide. 
This study will compare the safety of edoxaban with the standard of care (SOC) treatment in 
pediatric subjects with cardiac disease who need anticoagulation to prevent primary and 
secondary thromboembolic disease. Further data on edoxaban development are provided in the 
most recent Investigator’s Brochure5.  
1.3. 
Risk/Benefit 
Although pediatric subjects are at less risk than adults for the development of thromboembolic 
event (TE), embolic disease remains an uncommon condition, but it does occur and is well 
described in children and adolescents with or without risk factors. Thrombosis is an increasingly 
recognized complication occurring primarily in children with serious underlying conditions and 
most often associated with IV catheters,6 and is also recognized in neonatal and pediatric practice 
due to more sophisticated diagnostic tools being available. In children with cardiac disease, 
thromboembolic disease develops as a result of altered hemodynamics, prosthetic materials, 
surgically damaged blood vessels, intravenous catheters, and cardiopulmonary bypass. To 
prevent this potential life-threatening complication, some categories of pediatric cardiac patients, 
including patients with heart failure, Fontan circulation, severe cardiomyopathy (Kawasaki 
disease), and mechanic heart valve prostheses, are treated with less advanced therapy such as 
VKAs or heparin which requires intensive therapeutic monitoring. 
Many children with CHD require long-term thromboprophylaxis to decrease the morbidity and 
mortality secondary to the thromboembolic phenomenon. The advances in medical and cardio-
surgical techniques have led to improved survival in children with CHD; thus, the overall use of 
anticoagulation has increased. The overall incidence of thrombotic complications in patients 
undergoing cardiac surgery for CHD remains difficult to evaluate due to a lack of data. Giglia et 
al2 showed an incidence of clinically evident TE of 3.6% of 1930 total cardiac operations 
performed. More recently, Manlhiot et al3 revealed that 11% of cardiac operations over a 39-
month period were complicated by TEs. 


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Symptomatic thrombotic manifestation is recorded in 0.07/10,000 children, 
5.3/10,000 admissions of children and 24/10,000 admissions of newborns to intensive care 
units.1,7,8 According to the U.K. registry (British Pediatric Surveillance Unit), the estimated 
incidence of thromboembolic events was 0.07/10,000 children (excluding stroke), with 89% 
having venous involvement7. Besides the greater awareness, an objective increase in childhood 
thrombosis is attributed to medical advances in the treatment of critically ill patients. This 
seemingly contradictory observation is readily explained by the increasing use of central 
catheterization and innovative interventional procedures in the treatment of premature infants, 
neonates and older children who are critically ill, suffering from complex cardiac defects, and 
from malignant disease, respectively.  
Safety and effectiveness of edoxaban development is an ongoing program with 2 Phase 3 studies 
in the pediatric population (venous thromboembolism [VTE-U312 study] and arterial 
thromboembolism [ATE-U313 study]). In principle, based on current adult data obtained on 
edoxaban, edoxaban is also considered to be suitable for the pediatric population and supported 
by the FDA and EMA request for pediatric studies in select populations.  
The DU176b-A-U157 study (currently ongoing in the US, Canada, and Rest of the World 
[ROW]) will evaluate and establish the pharmacokinetics (PK), the pharmacodynamics (PD), the 
safety and tolerability of edoxaban in pediatric patients following single-dose oral 
administration. It will also evaluate the palatability of the liquid oral suspension of edoxaban. 
Pediatric patients who are at risk of thromboembolic events and may need anticoagulation are 
eligible for inclusion in the study. The goal of this study is to identify pediatric doses that are age 
appropriate and provides comparable exposure to adult efficacious doses to guide dose selection 
for the Phase 3 studies in a pediatric population who have confirmed VTE (U312 study) or 
patients with cardiac disease at risk of thromboembolic events (U313 Study) which require 
anticoagulant therapy.  
The dose for 3 of the 5 age cohorts 12 to <18, 6 to <12, and 2 to <6 years has been defined from 
the U157 study, and age cohort enrollment in the U312 VTE study and U313 will be sequential 
based on the availability of data derived from U157. Note: doses for age cohorts 6 months to <2, 
and 38 weeks gestation to <6 months) need to be defined. No safety concerns related to study 
drug have been observed in these subjects. In addition, approximately 135 subjects (12 to <18 
years) and 35 subjects (6 to <12 years) as of April 2019 in the Phase 3 U312 VTE study have 
been enrolled without clinical sequelae as reviewed by the Independent Data Monitoring 
Committee (IDMC).  
There are potential benefits for trial participation as well as receipt of the study drugs in this 
open label design, as patient compliance and lifestyle will be improved by taking an oral 
medication compared to an injectable (enoxaparin) or and VKA which has therapeutic 
monitoring requirements and potential food interactions. Indirect benefits to the patients enrolled 
in this trial are the free medical tests received at screening and during the study. The data derived 
from this study could potentially benefit pediatric patients when the study data is disclosed and 
becomes publically available or lead to a possible update of the edoxaban drug label for pediatric 
use. 
The safety monitoring practices employed by this protocol, DU176b-C-U313, (ie, physical 
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are considered adequate to protect the patients’ safety. The IDMC can recommend termination of 
the study based on concern about significantly higher bleeding risk relative to one of the study 
arms, concern about drug-induced liver injury or any other safety concern based on benefit/risk 
evaluation. Therefore, any risk associated with participation in this trial is fully evaluated during 
the course of the trial by an IDMC to ensure patient risk is minimized.  
In conclusion, for the individual pediatric patient, any benefit associated with participation in this 
trial is based on the confirmed efficacy and safety profile of edoxaban compared to SOC in the 
adult population from large Phase 3 studies, and the predicted benefit for the overall pediatric 
population. Any risk is minimized, as the trial is an open label design, is highly monitored by an 
IDMC and associated risks controlled and evaluated for the individual patient. Indirect benefits 
to the patients enrolled in this study are the free medical tests received at screening and during 
the study. However, the data derived from this study could potentially benefit pediatric patients if 
it leads to an extension of the edoxaban label. This research may give rise to new or better drug 
treatments for this vulnerable patient population. The information from this study may benefit 
other pediatric patients in the future. 


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2. 
STUDY OBJECTIVES, HYPOTHESIS AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective is to compare the safety of edoxaban with the 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) bleedings per International Society on Thrombosis and Haemostasis [ISTH] 
definition1 occurring in the Main Treatment Period: from the date of first dose of study drug to 
Month 3 Visit, or to the date of last dose of study drug plus 3 days if study treatment is 
discontinued, whichever is earlier.  
2.1.2. 
Secondary Objectives 
2.1.2.1. 
Key Secondary Objectives 
The key secondary objectives are:  
 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, systemic embolic event (SEE), myocardial infarction (MI), 
and asymptomatic intracardiac thrombus identified by cardiac imaging occurring 
from randomization to Month 3 Visit. 
 To compare the safety of edoxaban against SOC with regard to all bleedings which 
occur in the Main Treatment Period: from the date of first dose of study drug to 
Month 3 Visit, or to the date of last dose of study drug plus 3 days if study treatment 
is discontinued, whichever is earlier. 
 To compare the efficacy of edoxaban against SOC with regard to death as a result of a 
TE occurring from randomization to Month 3 Visit 
 To compare edoxaban against SOC with regard to all-cause mortality from 
randomization to Month 3 Visit. 
 To assess the safety of edoxaban with regard to the combination of major and CRNM 
bleedings occurring during the Extension Period (from Month 3 Visit to last dose plus 
30 days). 
 To assess the efficacy of edoxaban with regard to the development of symptomatic 
TE or asymptomatic intracardiac thrombus identified by cardiac imaging occurring 
during the Extension Period.  
 To assess the safety of edoxaban with regard to all bleedings occurring during the 
Extension Period. 
 To assess the efficacy of edoxaban with regard to death as a result of a TE occurring 
during the Extension Period.  


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 To assess the efficacy of edoxaban with regard to all-cause mortality occurring during 
the Extension Period. 
 To evaluate the population pharmacokinetics and pharmacodynamics of edoxaban in 
relation to the efficacy and safety endpoints in subjects with cardiac conditions at risk 
of TE. 
2.1.2.2. 
Other Secondary Objectives 
Not applicable. 
2.1.3. 
Exploratory Objectives 
The exploratory objectives are: 
 To assess the quality of life (QOL) using validated questionnaires. 
 To compare the intra-patient safety (Investigator reported bleeding) and efficacy 
(Investigator reported TE) during the Main Treatment Period compared with the prior 
treatment occurring within 3 months of randomization.  
 To compare edoxaban regimen with available existing historical data based on 
literature review and search for registered clinical trials with similar endpoints. 
 To analyze the primary prevention and secondary prevention of TE. 
2.2. 
Study Hypothesis 
This study is designed to assess the hypothesis that the administration of edoxaban will be at 
least as safe as the current SOC (unfractionated heparin [UFH] or LMWH and/or VKA) with 
regard to the combination of major and CRNM bleedings after 3 months of therapy in pediatric 
subjects with cardiac disease at risk of thromboembolic events.  
2.3. 
Study Endpoints 
All safety and efficacy endpoints described will be adjudicated in a blinded manner by the 
Clinical Events Committee (CEC). An Independent Data Monitoring Committee (IDMC) will 
monitor safety throughout the duration of the study. 
2.3.1. 
Primary Safety Endpoint 
The primary safety endpoint is a combination of major bleeding events and CRNM bleeding 
events per ISTH definition, occurring during the Main Treatment Period: from the date of first 
dose of study drug to the Month 3 Visit, or to the date of last dose of study drug plus 3 days if 
study treatment is discontinued, whichever is earlier.  
2.3.2. 
Secondary Safety Endpoint(s) 
The secondary safety endpoints are:  
 All bleeding events occurring during the Main Treatment Period: from the date of 
first dose of study drug to the Month 3 Visit, or to the date of last dose of study drug 
plus 3 days if study treatment is discontinued, whichever is earlier. 


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 A combination of major and CRNM bleedings from the day after Month 3 Visit to the 
date of the last dose of study medication plus 30 days for subjects who participate in 
the Extension Period. 
 All bleeding events from the day after the Month 3 Visit to the date of last dose of 
study medication plus 30 days for subjects who participate in the Extension Period. 
2.3.3. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 The combination of symptomatic TE in the systemic arterial or venous pathways 
including DVT, PE, stroke, intracardiac thrombus, SEE, and MI, and asymptomatic 
intracardiac thrombus identified by cardiac imaging, that occur from randomization to 
the Month 3 Visit.  
 Deaths as a result of TE that occurs from randomization to the Month 3 Visit. 
 All-cause mortality from randomization to the Month 3 Visit. 
 The combination of symptomatic TE in the systemic arterial or venous pathways and 
asymptomatic intracardiac thrombus identified by cardiac imaging, which occur from 
the day after the Month 3 Visit to the date of the last dose of study drug plus 30 days 
for subjects who participate in the Extension Period.  
 Deaths as a result of TE that occurs from the day after Month 3 Visit to the date of the 
last dose of study drug plus 30 days for subjects who participate in the Extension 
Period. 
 All-cause mortality from the day after the Month 3 Visit to the date of the last dose of 
study drug plus 30 days for subjects who participate in the Extension Period. 
2.3.4. 
Pharmacokinetic (PK)/Pharmacodynamic (PD)/Biomarker Endpoint(s) 
Plasma concentrations of edoxaban and its metabolite, D21-2393, will be assessed in subjects 
who receive at least 1 dose of edoxaban treatment and have measurable concentrations of 
edoxaban and/or D21-2393. Population PK analysis will be conducted to characterize the PK 
profiles of edoxaban in this target subject population.  
The PD biomarkers of coagulation, PT, activated partial thromboplastin time (aPTT), and anti-
activated Factor X (FXa), will be assessed as secondary endpoints in edoxaban-treated subjects. 
Other biomarkers may be tested related to coagulation and/or edoxaban’s mechanism of action. 
2.3.5. 
Quality of Life Assessment 
A pediatric QOL questionnaire will be issued at randomization and at the end of the Main 
Treatment Period to assess such categories as: health and activities, feelings about themselves, 
relationships with others, and school behavior. Note the QOL can be filled out by either a parent 
or the study participant. The same person should complete the QOL at Month 3. 
PedsQL version 4.0, generic core scale will be used in the study. 


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The following questionnaires will be used: 
 Adolescent (13-18) Self report  
 Adolescent (13-18) Parent report 
 Child (8-12) Self report 
 Child (8-12) Parent report 
 Young child (5-7) Self report 
 Young child (5-7) Parent report 
 Toddler (2-4) Parent report 




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The study includes 2 periods.  
 The Main Treatment Period is defined as the time from randomization, until the end 
of Month 3 of treatment.  
 Subjects who discontinue treatment from the Main Treatment Period prior to 
Month 3 will continue to be followed monthly according to the Schedule of 
Events (Appendix 17.1) through the Month 3 visit (Visit 5), and have a 30-day 
Follow-Up Visit. If treatment discontinuation occurs prior to Month 2 visit, the 
30-day Follow-Up Visit will occur on the same day as the Month 3 visit.  
 Subjects who complete the Main Treatment Period (Month 3) but do not continue 
into the Extension Period will have a Month 3 Visit and a Follow-Up Visit, 30 
days after last dose of study drug and be discontinued from the study. 
 Subjects who withdraw from the study prior to Month 3 (meaning the subject can 
no longer participate in the study due to withdrawal consent), will have a Follow-
Up phone call 3 months from the date of randomization to ascertain any events 
(TE and/or bleeding events) that may have occurred since withdrawal. 
 The Extension Period is discretionary for the subject based on the Investigator 
judgment of risk burden and will include treatment from the end of the Main 
Treatment Period (Month 3, Visit 5) up through the end of Month 12 (Visit 8).All 
subjects entering the Extension Period will be given edoxaban for the duration of the 
Extension Period. 
 After Month 3, all subjects will be transitioned to edoxaban at the appropriate 
dose for their age and weight at informed consent. 
 Subjects who discontinue the treatment and study at any time after Month 3 will 
have a Discontinuation Visit performed with a subsequent 30-day Follow-Up. 
 Subjects who complete Extension Period treatment at Month 12 (Visit 8) will 
have a Follow-Up Visit, 30 days after last dose of study drug (Visit 9). 
Subjects who require anticoagulant treatment after discontinuation of the study treatment at any 
time will be transitioned to a therapy as determined by the Investigator (Appendix 17.7). 
About 150 subjects from sites selected globally will be randomized in a 2:1 ratio 
(edoxaban:SOC, respectively) ratio into this study.  
Subjects from 1 to <18 years of age will be enrolled in the study as soon as the dosing regimen is 
established for each age cohort in the Phase 1 single-dose U157 study. U157 has 5 dosing age 
cohorts that are similar to the U313 study: 
 Ages 12 to <18 years  
 Ages 6 to <12 years  
 Ages 2 to <6 years  


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 Ages 6 months to <2 years 
(In Cohort 4 [6 months to <2 years], enrollment may open after the protocol data 
requirement for IDMC review for subjects less than 1 year old is met and the IDMC 
reviews and approves the data. Sites will be notified that enrollment of 6 month olds 
to <1 year olds may also open.)  
 Ages birth to <6 months.  
A review of safety data of 10%, 25%, 50%, and 75% of subjects completing the Main Treatment 
Period of 3 months will be performed on a routine basis by the Independent Data Monitoring 
Committee (IDMC). In addition, the IDMC will review the edoxaban exposure analysis from the 
U157 study in addition to the safety data from each age cohort to approve the proposed dose for 
the same age cohort in the U313 study. 
Additionally, subjects less than 1 year of age will be admitted to the study after review by the 
IDMC of safety data of 50% of subjects in the 1 to <18 years of age group who have completed 
the Main Treatment Period of 3 months (50 subjects in edoxaban arm and 25 subjects in SOC 
arm).  
3.3. 
End of Study 
This study will continue to randomize subjects until approximately 150 subjects (100 edoxaban- 
and 50 SOC-treated subjects) complete at least 3 months of treatment. All subjects in the 
Extension Period will complete treatment as judged by the Investigator after the last subject is 
randomized and completes 3 months of treatment.  
Primary safety endpoints are achieved during the first 3-month treatment period, ie, safety 
(bleeding) events occur across both treatment groups for the safety analysis set during the first 3-
month treatment period anytime from the date of first dose of study drug through the final Month 
3 Visit in all randomized subjects who receive at least one dose of randomized study drug. Based 
on the End of Randomization date a global End of Treatment (EOT) date will be established that 
ensures a minimum of 3 months of treatment for the last subject(s) randomized to study. All 
subjects must permanently discontinue study treatment on or before the EOT date. A final 
Follow-Up Visit date will be set 1 month following the EOT date. All subjects must complete 
their Follow-Up Safety Visit and permanently discontinue study on or before the Follow-Up 
Visit date. All subjects that discontinue treatment at Month 3 based on EOT will be placed on 
SOC at Investigator discretion. All safety and efficacy events will be evaluated by the CEC. 
Adjudicated results will be the basis for the final analyses. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be eligible for the study: 
1. Children with cardiac diseases who are at risk for thromboembolic complications and 
require at least 3 months antithrombotic anticoagulant prophylaxis. 
Either one of the following criteria may apply: 
a. Children with cardiac disease who have a history of cardiac shunt 
occlusion/thrombosis, with shunt still in place (secondary prevention). 
OR 
b. Children with cardiac disease who require (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 Thrombosis1. Some examples of cardiac conditions at risk of thrombosis 
are Fontan surgery, heart failure, Kawasaki disease, and Blalock-Taussig and Glenn 
surgery.  
2. Male or female children 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. 
3. 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 with edoxaban 
treatment. Pediatric subjects 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. 
4. Female subjects of childbearing potential must test negative for pregnancy at 
Randomization and must consent to avoid becoming pregnant by using a locally 
approved contraception method throughout the study. For locally approved contraceptive 
methods, see Appendix 17.3. 
5. If the subject has a history of a TE that meets all of the following criteria: 
 Old, organized and/or resolved per the discretion of the Principal Investigator 
(confirmation of an old, organized and or resolved TE is not required by any imaging 
studies), and 
 The subject is asymptomatic, and 
 The subject continues to require at least 3 months of anti-coagulation treatment, and 
 There is no intracardiac thrombus or thrombi on the screening echo, and  
 All other inclusion and exclusion criteria are met. 


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4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Subjects with a history of the following up to randomization: 
 Symptomatic venous or arterial TE 
 Asymptomatic venous or arterial TE found by routine imaging 
 Asymptomatic intracardiac thrombosis confirmed by an echocardiogram during study 
screening period. 
 Note: Valid echocardiograms are defined here as images taken within 5 weeks 
prior to Randomization Visit. 
2. Subjects with mechanical heart valves. 
3. Subjects with active bleeding or high risk of bleeding contraindicating treatment with 
anticoagulant. 
4. Subjects with a contraindication to the use of heparin (UFH or LMWH) and/or VKA (see 
Appendix 17.4). 
5. Co-administration of antithrombotic therapy is contraindicated in edoxaban arm and SOC 
arm except for low dose aspirin defined as 1 to 5 mg/kg/day with maximum of 100 
mg/day (see Appendix 17.5). 
6. Administration of rifampin is prohibited during the study and subjects on concomitant 
use of rifampin are excluded (see Appendix 17.5.6). 
7. a) Subjects with severe hepatic impairment or hepatic disease associated with 
coagulopathy (eg, acute hepatitis, chronic active hepatitis, and cirrhosis). 
b) Subjects with ALT >5 × the upper limit of normal (ULN) or total bilirubin (TBL) >2 × 
ULN with direct bilirubin >20% of the total at Screening.  
c) Subjects with aPTT >50 seconds or international normalized ratio [INR] >2.0 not 
related to anticoagulation therapy at Screening. 
8. Subjects with estimated glomerular filtration rate (eGFR) <30% of normal for age and 
size (see Appendix 17.9). 
9. Subjects with stage 2 hypertension defined as blood pressure (BP) systolic and/or 
diastolic confirmed >99th percentile plus 5 mmHg (see Appendix 17.10). 
10. Subjects with thrombocytopenia (thrombocytes <50 × 109/L). 
11. Subjects with Fontan procedure with a history of or signs/symptoms suggestive of 
protein-losing enteropathy. 
12. Subjects with a life expectancy less than the expected study duration (3 months). 
13. Subjects who are known to be pregnant or breastfeeding. 


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14. Subjects who are not using an approved method of contraception (see Appendix 17.3). 
15. 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 identified in Appendix 17.6. 
16. Subject who participated in another interventional clinical study or treated with an 
experimental therapy with less than a 30-day wash-out period prior to the Screening 
Visit. 
17. If any imaging is performed prior to randomization and results show a newly detected 
unorganized thrombus, these subjects are NOT eligible for the study. 
18. Hypersensitivity to the active ingredient or to any of the excipients of any components of 
the trial treatment. 
19. Patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome 
who are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 
2-glycoprotein I antibodies. 
4.3. 
Additional Requirements 
4.3.1. 
Stopping Rules for Study: 
An Independent Data Monitoring Committee (IDMC) may recommend termination of the study. 
Termination may be made for any of the following reasons: 
 Concerns about significantly higher bleeding risk relative to one of the study arms, 
 Concerns about drug-induced liver injury,9  
 Any other safety concerns based on benefit/risk evaluation by the IDMC. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Groups 
All subjects will be assessed for eligibility in the study in accordance with the 
inclusion/exclusion criteria. Eligible subjects will be stratified and randomized as follows: 
 All eligible subjects will be stratified by:  
Type of underlying heart disease: 
 Kawasaki disease 
 Fontan surgery 
 Heart failure (HF)  
 Others (which can include post-surgical procedures for congenital heart disease 
other than Fontan surgery) 
Subjects with underlying disease other than Kawasaki will be further stratified by 
concomitant use of low dose aspirin (1 to 5 mg/kg/day). 
 Randomized in a 2:1 ratio (edoxaban:SOC, respectively) into 1 of 2 treatment arms: 
 Edoxaban-treatment arm: subjects will receive a selected dose of edoxaban  
OR 
 SOC-treatment arm: subjects will receive SOC anticoagulant according to clinical 
site’s SOC treatment, as follows (alone or in combination): 
 Heparin, including UFH or LMWH  
 Vitamin K antagonist (VKA) with potential bridging with heparin based therapy 
until VKA INR is in therapeutic range 
After Month 3, all subjects who continue in the Extension Period and are on SOC will be offered 
edoxaban treatment and dosed according to their cohort age at the time of subject consent. 
During the extension period of the study, check the body weight prior to dosing and adjust 
dosage accordingly. Frequency of dosage changing is up to the Investigator’s discretion. 
Subjects from 1 to <18 years of age will be enrolled in the study as soon as the dosing regimen is 
established for each age cohort in the Phase 1 single-dose U157 study. 
Additionally, subjects less than 1 year of age will be admitted to the study after review by the 
IDMC of safety data of 50% of subjects in the 1 to <18 years of age group who have completed 
the Main Treatment Period of 3 months (50 subjects in edoxaban arm and 25 subjects in SOC 
arm).  
Subjects younger than 6 years of age will only receive edoxaban granules for oral suspension, 
which will give more flexibility to adjust mg/kg dose. Doses for all age groups will be selected to 
elicit target exposures comparable to those achieved from the adult Phase 3 study of 60 mg. 


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Table 5.1 indicates the edoxaban doses to be given for subjects of the ages 2 to <18 years of age. 
Doses for all subsequent age cohorts will be by separate notification to the investigative sites 
outside the content of this protocol after the IDMC has approved the proposed edoxaban doses 
and safety data from the U157 study. 
Doses for Cohorts 1, 2 and 3 have been established. Doses for the remaining subsequent age 
cohorts will be by separate notification to the investigative sites outside the content of this 
protocol after the IDMC has approved the proposed edoxaban doses and safety data from the 
U157 study.  
Study treatment should be administered on the same day as randomization (Day 1) if INR is ≤2.5 
for subjects receiving VKA prior to randomization. 
5.1.1.1. 
Edoxaban-Treatment Arm (Randomization through Month 12, and All SOC 
Subjects Converted to Edoxaban after Month 3) 
Edoxaban treatment will be packaged and dispensed to the subject on a monthly visit schedule. 
For subjects who cannot pick up their study therapy on a monthly basis, accommodations will be 
made to allow the Investigator to distribute up to a 3-month supply of study drug to match the 
scheduled study visit interval. Edoxaban will be given orally at the appropriate dose depending 
on the results of the ongoing U157 study.  
Cohort 1 (12 to <18 years old) and Cohort 2 (6 to <12 years old) will receive tablets (15 and/or 
30 mg strength, see Table 5.1) or offered granules for oral suspension if swallowing is an issue. 
Subjects <2 years of age will take edoxaban granules for oral suspension which will provide 
more flexibility to adjust mg/kg dose. Subjects will be instructed to take the edoxaban dose 
orally once a day, at the same time every day, preferably in the morning, with or without food. 
Tablets should be swallowed with a glass of water. One bottle of edoxaban granules should be 
used for each dosing day. The recommended dosing for the 12 to <18, 6 to <12, and 2 to <6 year 
olds is shown in Table 5.1. 
Dosing recommendations for the lower age cohorts will be provided as the U157 single-dose 
edoxaban study completes the PK exposure analysis for similar age cohorts. Doses for all 
subsequent age cohorts will be by separate notification to the investigative sites outside the 
content of this protocol. 
During the extension period of the study, check the body weight prior to dosing and adjust 
dosage accordingly. Frequency of dosage changing is up to the Investigator’s discretion. 


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Table 5.1: 
Edoxaban Dose Recommended for 3 Cohorts (12 to <18 years, 6 to <12 years, 
and 2 to <6 years) 
Age 
Body Weight at 
Randomization or 
at Subsequent 
Visit 
Dose 
(Tablet) 
Dose (Suspension) 
(6 mg/mL 
concentration)c 
Dose Reductiona 
12 to <18 yearsb 
(At date of consent) 
≥60 kg 
60 mg QD 
10 mL 
45 mg QD 
≥30 and <60 kg 
45 mg QD 
7.5 mL 
30 mg QD 
<5th Percentile for 
Agec 
30 mg QD 
5 mL 
NA 
6 to <12 years 
(At date of consent)d 
≥60 kg 
60 mg QD 
10 mL 
45 mg QD 
<60 kg 
Dosed based on 
mg/kge 
NA 
1.2 mg/kg with a 
maximum dose of 45 
mg 
0.8 mg/kg with a 
maximum dose of 
45 mg 
2 to <6 years 
(At date of consent) 
Dosed based on 
mg/kg 
NA 
1.4 mg/kg with a 
maximum dose of 45 
mg 
0.7 mg/kg with a 
maximum dose of 
24 mg 
Abbreviations: eGFR = estimated glomerular filtration rate; NA = not applicable; QD = once a day 
a Conditions for dose reduction:  
If a subject requires concomitant administration of P-glycoprotein (P-gp) inhibitor (Appendix 17.6.1), the 
edoxaban dose will be reduced during P-gp administration and re-established to the original dose once P-gp 
inhibitor administration had concluded.  
Edoxaban dosage regimen will be reduced permanently for subjects with moderate renal impairment for the 
subject’s age and size at randomization as determined by the age appropriate formula: Cockcroft-Gault 
equation for pediatric subjects ≥12 years of age and modified Schwartz equation for pediatric subjects <12 
years of age). Refer to Appendix 17.9 for eGFR values below which dose reduction should be implemented.  
If a subject experiences a change in renal function from normal to eGFR ≥30% to ≤50% after 
randomization, the measurement will be repeated within 1 week. If the repeat measurement confirms the 
decrease, the edoxaban dose reduction will be permanent even if the subject experiences an improvement 
in the eGFR during the course of the study. 
b Dose reduction due to body weight applies only for fixed doses in subjects 12 to <18 years of age:  
If body weight increases or decreases from the categories of weight defined at consent, the subject will be dose 
adjusted. Subjects who are ≥60 kg of body weight at consent and drop below that body weight will receive 45 
mg dose at any subsequent visit. Subjects ≥30 and <60 kg at consent increasing their weight to ≥60 kg will 
increase their dose to 60 mg. 
c Edoxaban dosage regimen will be reduced permanently for subject with body weight <5th percentile for age. Refer 
to Appendix 17.11. 
d Per Principal Investigator’s discretion, for subjects in Cohort 2 that require either 45 mg or 60 mg dose, the 
Principal Investigator may use edoxaban tablets instead of granules, if they wish.  
e Edoxaban granulation will be diluted with 8 mL water to provide a concentration of 6 mg/mL dosing suspension.  
If body weight increases or decreases from the categories of weight defined at consent, the subject will be dose 
adjusted. Subjects who are ≥60 kg of body weight at consent and drop below that body weight will receive 45 
mg dose at any subsequent visit. Subjects ≥30 and <60 kg at consent increasing their weight to ≥60 kg will 
increase their dose to 60 mg. 
Note: Dose is based upon weight at corresponding visit. 
For subjects without prior anticoagulant therapy, edoxaban may be started the day of 
randomization (Day 1).  


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For subjects who received VKA treatment prior to randomization and are randomized to 
edoxaban, VKA treatment will be discontinued the day before randomization and edoxaban dose 
will be initiated when an INR ≤2.5 is reached. 
5.1.1.2. 
Standard of Care Treatment Arm (Randomization to Month 3). 
SOC randomized subjects will be treated with SOC though Month 3 (Visit 5) and then offered 
edoxaban through Month 12. SOC treatment will be packaged and dispensed to the subject on a 
monthly visit schedule. After Month 3, all subjects will be transitioned to edoxaban at the 
appropriate dose for their age and weight. Locally sourced SOC is the preferred option for this 
study, either by the Investigator or, alternatively local supply depots within each country that 
provide SOC directly to the clinical sites. However, centrally sourced SOC can be provided 
when the country or clinical site requirements deem it necessary. In the case of centrally sourced 
treatment, the Sponsor will only provide enoxaparin as LMWH and warfarin as VKA.  
For subjects who did not receive VKA treatment prior to randomization and are randomized to 
SOC with VKA, VKA treatment may be started on the day of randomization (Day 1).  
It is the Investigator’s discretion based on his/her local practice and on the subject’s underlying 
cardiac disease to consider if heparin bridging is necessary when initiating VKA post 
randomization until an INR between 2.0 and 3.0 is reached. Heparin bridging will be provided by 
the Investigator. 
5.1.2. 
Method of Treatment Allocation 
Eligible subjects will be stratified as mentioned in Section 5.1.1. An independent biostatistician 
will generate the randomization schedule in accordance with the operating procedure for 
allocating study drug.  
At randomization, the Investigator provides the Interactive Web/Voice Response System (IXRS) 
with the clinical site number and the subject’s presenting diagnosis and date of birth.  
Dose will be reduced for subjects based on the following criteria:  
 eGFR is 30-50% of normal for age and size (Appendix 17.9 ). If a subject experiences 
a change in renal function from normal to eGFR ≥30% to ≤50% after randomization, 
the measurement will be repeated within 1 week. If the repeat measurement confirms 
the eGFR ≥30% to ≤50%, the edoxaban dose will be reduced permanently. 
 Subject is receiving concomitant treatment with P-gp inhibitors. The dose will be 
reduced while on P-gp inhibitor and re-established to original dose once the 
concomitant medication is stopped (Appendix 17.6.1). 
 Body Weight: 
 For subjects 12 to <18 years old  with body weight <5th percentile of subject’s 
age (see Appendix 17.11), edoxaban doses will be permanently changed. 
 For subjects 12 to <18 years old  with body weight ≥60 kg, will receive 
edoxaban 60 mg. However, if the body weight is ≥30 - <60 kg, edoxaban dose 
would be 45 mg daily. If the patient body weight ≥60 kg, then edoxaban dose 
would be escalated to 60 mg daily. 


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 For subjects <12 years old: Doses will be provided by mg/kg or a dose may be 
suggested, subsequent to exposure modeling, based on an age range (see 
Table 5.1). 
 
The IXRS will assign the unique subject identification number, allocate the treatment group 
assignment for the subject and provide the appropriate drug supply kit number(s). 
A fax or e-mail will be sent by the IXRS to provide the appropriate drug supply kit number(s). 
The fax or e-mail will also provide a calendar with dates of subsequent prescheduled visits and 
drug resupply. 
5.1.3. 
Blinding 
Not applicable. 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable.  
5.2. 
Study Drug(s) 
5.2.1. 
Description 
The study drug for this study is edoxaban (DU-176b) and SOC anticoagulants (UFH/LMWH and 
VKA). The active ingredient is edoxaban tosylate and the international non-proprietary name is 
N-(5-Chloropyridin-2-yl)-N’-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-
tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl] oxamide mono (4-
methylbenzenesulfonate) monohydrate. 
5.2.1.1. 
Edoxaban (Randomization through Month 12) 
Edoxaban will be packaged and supplied to the subject on a monthly visit schedule as tablets (15 
and/or 30 mg strength) or granules for oral suspension (60 mg strength) even though after Month 
3 the clinic visitation schedule is every 3 months. For subjects who cannot pick up their study 
therapy on a monthly basis, accommodations will be made to allow the Investigator to distribute 
up to a 3-month supply of study drug to match the scheduled study visit interval. 
Subjects will be instructed to take edoxaban (tablets or granules) orally once a day, at the same 
time every day, preferably in the morning, with or without food. One bottle of edoxaban granules 
will be used for each dosing day. Tablets should be swallowed with a glass of water.  
The doses will be dispensed as follows: 
For subjects 12 to <18 years old: 
 A 60 mg dose will be dispensed as two 30 mg tablets or 10 mL from an individual 
bottle of oral suspension 60 mg 
 A 45 mg dose will be dispensed as one 30 mg tablet plus one 15 mg tablet or 7.5 mL 
from an individual bottle of oral suspension 60 mg 


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 A 30 mg dose will be dispensed as one 30 mg tablet or 5 mL from an individual bottle 
of oral suspension 60 mg  
 Doses provided by the granulation formulation will be dispensed with a dosing 
syringe according to the recommended dose shown in Table 5.1. 
 If a subject does not have the capacity to swallow tablets in the 12 to <18 year and 6 
to <12 year old groups, the tablets may be crushed and served with applesauce or 
mixed with 2 to 3 ounces of water and immediately administered by mouth or through 
an existing gastric tube, if needed. 
For subjects 6 to <12 years old: 
 60 mg dose will be dispensed as two 30 mg tablets or as 10 mL from an individual 
bottle of oral suspension 60 mg. 
 45 mg dose will be dispensed as one 30 mg tablet plus one 15 mg tablet or as 7.5 mL 
from an individual bottle of oral suspension 60 mg. 
 Dose other than 45mg and 60mg provided by the granulation formulation will be 
dispensed with a dosing syringe according to the recommended dose shown in 
Table 5.1. One bottle will be used for each daily dose. 
5.2.1.2. 
Standard of Care (Randomization through Month 3) 
Treatment with SOC will only occur through Month 3. After that time all subjects will be offered 
edoxaban at a dose appropriate for age and weight. Local sourcing will be the preferred option 
for SOC drugs, either by the Investigator or local depot providing locally utilized therapy to treat 
TE. The Sponsor will supply central sourcing as an alternative option to local SOC sourcing.  
Clinical supply will be packaged and dispensed to the subject on a monthly visit schedule.  
If local sourcing is used, the Investigator is allowed to utilize any UFH or LMWH, and/or VKA 
according to the SOC treatment specific to that clinical site (no strength restrictions).  
If central sourcing is used, only enoxaparin and warfarin will be supplied by the Sponsor at fixed 
doses as the LMWH and the VKA, respectively. If a subject is prescribed a dose of the LMWH 
or VKA different from the doses supplied, a combination of the various doses should be used to 
obtain the desired dose. Guidance on dosing and dispensing is provided in Appendix 17.2. 
Note: If standard practice for bridging VKA to therapeutic levels is achieved with a heparin 
(UFH or LMWH) based treatment, the clinical site will be responsible for providing the bridging 
therapy for subjects randomized to VKA. 
If required, the Sponsor will provide centrally sourced SOC treatment at the following fixed 
doses: 
 Enoxaparin (LMWH) will be provided as solution for SC injection in pre-filled 
syringes with only 60 mg/0.6 mL, 80 mg/0.8 mL, and 100 mg/1.0 mL concentration 
for injection, or as multiple dose vials (for subjects <20 kg).  
 Warfarin (VKA) will be supplied as tablets (0.5 mg, 1 mg, and 3 mg). Various doses 
will be available for INR maintenance in the therapeutic range of 2 to 3.  


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5.2.1.3. 
Aspirin 
Clinical sites or treating physicians will provide aspirin (as per local SOC practice). 
5.2.2. 
Labeling and Packaging 
5.2.2.1. 
Edoxaban 
Study drug will be provided in adequate quantity for study conduct and labeled in an open-label 
format. Study drug labels will include all information required by federal and local regulations. 
Edoxaban 15 and 30 mg tablets will be supplied by the Sponsor in an open-label format. The 
edoxaban 60 mg granules for oral suspension will be provided in glass bottles, as per visit 
schedule, for single dose administration. 
5.2.2.2. 
Standard of Care  
Standard of care sourced locally either by the Investigator or by a local depot providing SOC to 
the clinical site will have no modification in labeling or packaging. Hence, locally sourced SOC 
treatment will have a label identical to the procured drug. 
If required, centrally sourced SOC treatment will be presented in its commercial presentation 
with the clinical study over-label. SOC labels will include all information required by federal and 
local regulations. 
Note: If standard practice for bridging VKA to therapeutic levels is achieved with a heparin 
based treatment, the clinical site will be responsible for providing the bridging therapy if the 
subject is randomized to VKA. 
5.2.3. 
Preparation 
5.2.3.1. 
Edoxaban  
No special preparation will be required for the tablet formulation. However, if a subject does not 
have the capacity to swallow tablets in the 12 to <18 year old group, the tablets may be crushed 
and served with applesauce or mixed with 2 to 3 ounces of water and immediately administered 
by mouth or through an existing gastric tube, if needed. 
The edoxaban granules for oral suspension 60 mg will be provided in amber glass bottles (wide 
neck) with child-resistant caps. The edoxaban granules for oral suspension 60 mg formulation 
will be reconstituted with 8 mL of water to provide a 6 mg/mL liquid suspension. One bottle will 
be used for each daily dose. Instructions for reconstitution will be provided to the 
Investigator/designee and the caregiver. 
5.2.3.2. 
Standard of Care 
No special preparation will be required for locally (or centrally) sourced SOC. Instructions for 
daily use will be provided to the Investigator/designee. 


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5.2.4. 
Administration 
Study drug will be packaged and dispensed to the subject on a monthly visit schedule. For 
subjects who cannot pick up their study therapy on a monthly basis, accommodations will be 
made to allow the Investigator to distribute up to a 3-month edoxaban supply of study drug (for 
those continuing after Month 3 through Month 12) to match the scheduled study visit interval. 
Note that each monthly dispensing visit is not indicated in Table 17.1 because no additional 
procedures are expected at the monthly dispensing visits. 
Locally sourced study drug will be provided by the Investigator or through a depot within the 
country of the clinical site. If required, centrally sourced study drug will be shipped to the 
clinical sites, and the Investigator/designee will be responsible for dispensing the study drugs. 
The Investigator/designee will provide the subjects with product in sufficient quantity, plus 
overage, via IXRS dispensing until the next scheduled visit.  
The Investigator/designee will also instruct the subject on reporting study drug or SOC 
administration and accountability. Subjects who miss 1 dose of study drug or SOC will be 
instructed to skip that dose and take the next dose at their drug administration schedule. 
5.2.4.1. 
To Initiate Edoxaban Treatment at Randomization  
For subjects without prior anticoagulant therapy, edoxaban may be started the day of 
randomization (Day 1).  
For subjects who received VKA treatment prior to randomization and are randomized to 
edoxaban, VKA treatment will be discontinued the day before randomization and edoxaban dose 
will be initiated when an INR ≤2.5 is reached. It is per Investigator’s discretion based on his/her 
local practice and on the subject’s underlying cardiac disease to consider if heparin bridging is 
necessary during this period. Heparin bridging will be provided by the Investigator. 
If heparin bridging is used, edoxaban will be started as below:  
1. In case of bridging with a LMWH twice a day regimen, edoxaban dosing will start 
12 ± 3 hours after the last LMWH dose 
2. In case of bridging with a LMWH once a day regimen, edoxaban dosing will start 
24 ± 3 hours after the last LMWH 
3. In case of bridging with a UFH regimen, edoxaban dosing will start 4 ± 1 hour after the 
last UFH dose 
5.2.4.2  
Transition SOC-Treated Subjects during the Main Treatment Period to 
Edoxaban in the Extension Period  
For subjects who received VKA treatment edoxaban dosing will be initiated when an INR ≤2.5 is 
reached. This may occur as early as next day of the Extension Period.  
If the subject was originally randomized to UFH or LMWH, edoxaban will be started as below:  
1. In case of LMWH twice a day regimen, edoxaban dosing will start 12 ± 3 hours after the 
last LMWH dose 


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2. In case of LMWH once a day regimen, edoxaban dosing will start 24 ± 3 hours after the 
last LMWH 
3. In case of UFH regimen, edoxaban dosing will start 4 ± 1 hour after the last UFH dose 
5.2.4.3  
To Initiate SOC Treatment 
If the subject is randomized to the SOC treatment and they use locally sourced SOC, they will 
receive the following SOC anticoagulant treatment according to the clinical site’s usual treatment 
practice (alone or in combination): 
 LMWH (alone or with VKA) 
 UFH (alone or with VKA) 
 VKA (alone or with LMWH or UFH) 
For subjects who do not receive VKA treatment prior to randomization and are randomized to 
SOC with VKA, VKA treatment may be started on the day of randomization (Day 1).  
It is per Investigator’s discretion based on his/her local practice and on the subject’s underlying 
cardiac disease to consider if heparin bridging is necessary post-randomization until an INR 
between 2.0 and 3.0 is reached. Heparin bridging will be provided by the Investigator. 
If centrally sourced SOC treatment is required from the Sponsor, the subject will be treated as 
follows:  
 For subjects randomized to enoxaparin: Neonates or children receiving either once- or 
twice-daily therapeutic enoxaparin should be monitored as per local practice.  
 For subjects randomized to warfarin, it is recommended that the dose should be 
titrated to achieve a target INR of 2.0 to 3.0. It is per Investigator’s discretion based 
on his/her local practice and on the subject’s underlying cardiac disease to consider if 
heparin bridging is necessary during this period. Visits will be at the discretion of the 
Investigator and captured as unscheduled visits for data collection. Adjustment of the 
maintenance dose of VKA will be dependent on INR monitoring as follows:  
 INR  2.0 to 3.0, no change in dose 
 INR  1.1 to 1.4, increase dose by 20% 
 INR  1.5 to 1.9, increase dose by 10% 
 INR  3.1 to 3.5, decrease dose by 10% 
 INR >3.5, hold VKA until INR is <3.5, then decrease dose by 20% when 
restarted.  
To initiate SOC post screening, it is recommended to test infants and children every 4 weeks 
once a stable dose of VKA has been achieved. However, depending on the site’s clinical practice 
and PI’s discretion, the subjects can be tested at the physician’s discretion and/or according to 
local practice. More frequent INR testing is recommended in infants and children receiving VKA 
with any change in diet or medication or when an illness occurs. An unscheduled visit will need 


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to be performed to document the discretionary INR measurement and potential VKA dosage 
change as an unscheduled visit day. 
For subjects on LMWH or UFH, periodic assessment of therapeutic level is recommended. The 
most widely used laboratory assay for monitoring UFH or LMWH therapy is the aPTT and anti-
FXa activity. All testing for therapeutic monitoring after randomization will be conducted 
locally. 
Guidance on dosing and dispensing is provided in Appendix 17.2. 
5.2.5. 
Storage 
Edoxaban tablets and granules for oral suspension must be stored at 20° to 25°C (68° to 77°F) 
with excursions permitted to 15° to 30°C (59° to 86°F). 
SOC treatments must be stored as per labeled storage conditions. 
All drug supplies must be stored in a secure, limited access storage area under the recommended 
storage conditions. If storage conditions go outside of allowable excursions, Sponsor/Contract 
Research Organization (CRO) must be contacted. The excursions will be discussed with the 
Sponsor and CRO to determine what action is necessary.  
Storage temperatures must be recorded using devices such as a maximum/minimum 
thermometer. Temperature measurements will be recorded on a temperature log excluding 
weekends and holidays. 
5.2.6. 
Drug Accountability 
5.2.6.1. 
Edoxaban 
Edoxaban will be provided by the Sponsor. When a drug shipment is received, the Investigator 
or designee will confirm the amount and condition of the drug and confirm the appropriate local 
language in the label, drug expiration date, and temperature monitor readings. The Investigator 
or designee will also sign the Receipt of Shipment Form provided and the form should be 
returned as instructed on the form. The original form will be retained at the clinical site. In 
addition, the Investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment and quarantine the shipment until the resolution is obtained from the 
Sponsor. 
At the end of the study, or as directed, all drug products, including unused, partially used, or 
empty containers, will be destroyed, after full accountability. If drug destruction occurs at the 
clinical site, this must be approved in writing by the Sponsor and the Sponsor has received 
copies of the clinical site’s drug handling and disposition standard operating procedures (SOPs).  
For Sponsor provided drug, dosage form (ie, tablets and granule bottles) clinical site level 
accountability documentation is required as part of the disposition records of study drug. The 
dosage form site level accountability documentation should be appended to the Certificate of 
Destruction, if available. 
The study drug will only be returned to a designee as instructed by the Sponsor if the clinical site 
is unable to perform the products destruction. Study drug will be returned only after the study 
monitor has completed a final inventory to verify the quantity to be returned. The 


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return/destruction of products must be documented. At the end of the study, a final product 
reconciliation statement must be completed by the Investigator/designee and provided to the 
Sponsor.  
Dosage form (ie, tablets and granule bottles) clinical site level accountability documentation is to 
be included with each drug supply return shipment (or other returning facility, such as another 
depot). This is required as part of the receiving records for return shipments. 
All inventory forms must be made available for inspection by a Sponsor-authorized 
representative or designee and regulatory agency inspectors. The Investigator is responsible for 
the accountability of all used and unused study supplies at the clinical site. 
5.2.6.2. 
Standard of Care 
For both locally sourced SOC and Sponsor-provided SOC, a Drug Accountability Record will be 
used for the products. It may either be provided by the Sponsor or Sponsor representative, or the 
site may use a Sponsor approved form. The record must be kept current and must contain the 
dates and quantities of drug received from the central or local supply (for Sponsor provided 
therapy), subjects for whom the products was dispensed (identification number and/or initials or 
supply number as applicable), the date and quantity of study drug dispensed and remaining, if 
from individual subject drug units, as well as the initials of the dispenser. All unused drug and 
containers whether provided by the Sponsor or provided locally, must be brought back to the 
clinical site for accountability to support appropriate dosing instructions to the subject. 
At the end of the study, or as directed, all drug products, including unused, partially used, or 
empty containers, will be destroyed, after full accountability. If drug destruction occurs at the 
clinical site, this must be approved in writing by the Sponsor and the Sponsor has received 
copies of the clinical site’s drug handling and disposition SOPs). Locally sourced SOC should be 
destroyed at the clinical site. 
For Sponsor-provided and locally supplied drug, dosage form (ie, tablets and syringes) site level 
accountability documentation is required as part of the disposition records of study drug. The 
dosage form site level accountability documentation should be appended to the Certificate of 
Destruction, if available. 
The study drug will only be returned to a designee as instructed by the Sponsor if the clinical site 
is unable to perform the products destruction. Study drug will be returned only after the study 
monitor has completed a final inventory to verify the quantity to be returned. The 
return/destruction of products must be documented. At the end of the study, a final product 
reconciliation statement must be completed by the Investigator/designee and provided to the 
Sponsor.  
Dosage form (ie, tablet, granule bottles, and syringes) site level accountability documentation is 
to be included with each drug supply return shipment (or other returning facility, such as another 
depot). This is required as part of the receiving records for return shipments. 
All inventory forms must be made available for inspection by a Sponsor-authorized 
representative or designee and regulatory agency inspectors. The Investigator is responsible for 
the accountability of all used and unused study supplies at the clinical site. 


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5.3. 
Dose Interruptions and Reductions 
If a subject’s treatment with study drug must be interrupted for medical or surgical reasons (eg, 
hospital admission for an invasive procedure, a major medical condition, surgery, 
thrombocytopenia due to cytotoxic medication, or dental work); use of a prohibited concomitant 
medication; or other reasons (eg, temporary situation that prevents subject adherence with the 
study drug administration schedule, etc), the subject’s study drug should be resumed as early as 
the situation allows. Edoxaban should be discontinued for 24 hours prior to the initiation of the 
procedures.  
Subjects should be encouraged to restart study drug after an interruption except when absolutely 
contraindicated. The duration of study drug interruption can vary depending upon the individual 
circumstances, and study drug may be resumed regardless of the duration of time that it had been 
interrupted. Any subject who temporarily interrupts study drug more than 3 days will have the 
reason recorded in the electronic case report form (eCRF). 
Any study drug interruption due to an adverse event should be reported on the Adverse Event 
eCRF, even if it is less than 3 days. A patient may have multiple interruptions of treatment 
throughout their study participation. 
5.3.1. 
Edoxaban Dose Reduction 
During the treatment period, a subject may reduce the dose of edoxaban for any of the following 
reasons: 
 eGFR is 30-50% of normal for age and size (permanent dose reduction) 
(Appendix 17.9) 
 NOTE: If the repeat measurement confirms the decrease, the edoxaban dose will 
be reduced permanently. This dose reduction will be permanent even if the 
subject experiences an improvement in the eGFR during the course of the study. 
 Subject is receiving concomitant treatment with P-gp inhibitors (temporary dose 
reduction) 
 Body Weight: 
 For subjects 12 to <18 years old  with body weight <5th percentile of subject’s 
age (see Appendix 17.11), edoxaban doses will be permanently changed. 
 For subjects 12 to <18 years old  with body weight ≥60 kg, will receive 
edoxaban 60 mg. However, if the body weight is ≥30 - <60 kg, edoxaban dose 
would be 45 mg daily. If the patient body weight ≥60 kg, then edoxaban dose 
would be escalated to 60 mg daily. 
 For subjects <12 years old: Doses will be provided by mg/kg or a dose may be 
suggested, subsequent to exposure modeling, based on an age range (see 
Table 5.1). 
For subjects receiving P-gp inhibitors during the study treatment period, the dose of edoxaban 
will only be reduced during the administration of the concomitant P-gp inhibitor. Subjects 


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experiencing eGFR or body weight reduction will maintain their reduced edoxaban dose for the 
duration of the study. 
5.4. 
Method of Assessing Treatment Compliance 
Dosing compliance for subjects in the edoxaban treatment arm will be assessed by means of 
tablet/bottle counts remaining and/or drug packaging/bottles returned. All drug packaging will be 
returned at each subject visit and will be accountable including bottles with dilutions made for 
dosing. Administration of the study drug will be recorded in the case report form 
(CRF)/eCRF/Drug Accountability Record. As necessary, include method of compliance 
calculation based on the returned number of tablets/bottles. If zero tablets/bottles returned, ask 
subject whether any were disposed or thrown away, rather than taken orally. 
Subjects in the SOC (VKA) treatment arm will be monitored for compliance by measuring INR 
levels. Subjects in the SOC (UFH, LMWH) treatment arm will be monitored for compliance by 
measuring anti-FXa levels or aPTT. Compliance should be assessed routinely by the Investigator 
to ensure the adequate doses are taken (Table 17.1). Monitoring of heparin based treatment or 
VKA will be performed locally. 
5.5. 
Prior and Concomitant Medications 
Medications that the subject has taken within 30 days before screening will be recorded. In 
addition, anticoagulant and antiplatelet therapy will be recorded up to 3 months prior to 
randomization. 
The following drugs and devices (see Appendix 17.5) CANNOT be used during the entire study 
treatment period and their unavoidable use would require study drug therapy interruption unless 
specifically indicated for study drug discontinuation: 
 Anticoagulants, other than the assigned study drugs, by any route  study drug should 
be discontinued 
 Single or dual antiplatelet therapy with any antiplatelet agent is prohibited except for 
low dose aspirin defined as 1 to 5 mg/kg/day with maximum of 100 mg/day. If a 
clinical indication for antiplatelet therapy (other than low dose aspirin) arises after 
randomization, study drug should be temporarily interrupted and use of any other 
anticoagulation therapy is permitted at the physician’s discretion.  
 Chronic use of oral or parenteral non-steroidal anti-inflammatory drugs (NSAIDs) 
including both cyclooxygenase-1 and cyclooxygenase-2 inhibitors other than aspirin 
for ≥4 days/week. Use of NSAIDs via other routes (eg, topical, inhaled, intranasal, 
intraocular, etc) are not restricted (see Appendix 17.5.5). 
All P-gp inhibitors (please refer to Appendix 17.6.1 for a list of the most commonly used P-gp 
inhibitors) excluding amiodarone will require dose reduction of edoxaban.  
The Investigator is encouraged to contact a study physician (telephone number will be provided 
per country, per region; please refer to Study Manual for an appropriate phone number) if further 
guidance is needed. 


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Information regarding concomitant medications will be collected with start date, stop date, drug 
name, dose, and dosing regimen for population PK analyses at Month 1. 
5.6. 
Subject Withdrawal/Discontinuation 
Any subject who discontinues from the study treatment for any reason will have his or her study 
treatment discontinuation recorded.  
A subject may discontinue study treatment during the Main Treatment Period; however the 
subject should still remain as a study participant for scheduled visits through Month 3 (Visit 5). 
The subject should complete the subsequent 30-day Follow-Up Visit (Visit 9) regardless of 
whether they stop all anticoagulant therapy or are placed on a treatment that they were not 
assigned to at randomization.  
If a subject discontinues from treatment after Month 3 he/she will be discontinued from the study 
and should still receive a Discontinuation Visit and a 30-day Follow-Up Visit. 
5.6.1. 
Discontinuation from Treatment within the Main Treatment Period (Month 3) 
Early discontinuation of study drug is discouraged. However if, in the Investigator’s opinion, 
continuation of study drug would be detrimental to the subject’s well-being or in specific clinical 
situations (eg, liver function test [LFT] disturbances, severe renal insufficiency, TE, bleeding), 
the study drug can be stopped permanently.  
Subjects who discontinue treatment during the Main Treatment Period should return to the 
clinical site per the study procedure schedule (Table 17.1) for all remaining safety and efficacy 
assessments through the Month 3 visit (Visit 5) regardless of what treatment, if any, they may 
subsequently be taking. A 30-day Follow-Up Visit (Visit 9) will be required. A telephone call for 
Follow-Up assessment may be conducted in exceptional circumstances when the subject is not 
able or willing to present to the clinical site.  
The reasons for discontinuation from treatment must be documented. 
If a subject discontinues treatment prior to Month 3, the Investigator will complete and report the 
observations as thoroughly as possible at scheduled visits including the date of last treatment and 
the reason for discontinuation from study treatment though 3 months of observation.  
5.6.2. 
Discontinuation from Treatment and Study beyond Month 3 up to Month 12  
During the Extension Period (beyond 3 months treatment), all subjects who discontinue from the 
study treatment will also discontinue from the study and will return to the clinical site for a 
Discontinuation Visit (Visit 8) and a 30-day Follow-Up Visit (Visit 9) after the Discontinuation 
Visit.  
Note: Subjects in the Extension Period do not need to be followed through 12 months of study 
procedures and can discontinue from treatment and study per Investigator discretion at any time 
with a Discontinuation Visit after Month 3 and a 30-day Follow-Up Visit after the 
Discontinuation Visit.  
5.6.3. 
Reasons for Discontinuation from Study Treatment  
Subjects may discontinue the treatment for any of the following reasons: 


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1. End of requirement for anticoagulant therapy 
2. Reasons related to adverse events (AEs): 
 If initiating or continuing study drug places the subject at undue hazard as determined 
by the Investigator; 
 If the subject had a serious adverse event (SAE) or other safety concern that is related 
to study drug treatment as determined by the Investigator; 
 If the subject had a major bleeding event as determined by the Investigator; 
 If the subject has an aggravation or new occurrence of renal insufficiency with 
estimated eGFR <30% of normal for age and size (Cockcroft-Gault equation for 
pediatric subjects ≥12 years of age and modified Schwartz equation for pediatric 
subjects <12 years of age); 
 If the subject demonstrates hepatic test abnormalities including: 
 Elevation of alanine transaminase (ALT) and/or aspartate transaminase (AST) ≥3 
× ULN and TBL ≥2 × ULN simultaneously. 
 ALT and/or AST ≥8 × ULN requires an immediate interruption of study drug 
treatment and prompt repeat testing to confirm abnormality.  
 If the subject demonstrates clinical jaundice that requires an immediate interruption 
of study drug treatment and prompt repeat testing to confirm abnormality; 
 If the subject has any elevation of transaminases combined with clinical symptoms of 
liver injury; 
 If a subject discontinues study drug due to confirmed liver enzyme abnormalities or 
jaundice. The subject will have additional evaluations at the discretion of the 
Investigator as follows: 
 Hepatitis A, B, C, and E screening (anti-HAV IgM, HBsAg, anti-HCV plus viral 
titer, and evaluation for Hep E); 
 Abdominal ultrasound; 
 Antinuclear antibody (ANA) and anti-SmAb; 
 Cytomegalovirus (CMV); 
 Epstein-Barr virus (EBV); 
 Additional evaluations as deemed appropriate by the Investigator to exclude other 
causes of liver enzyme and TBL elevations. 
Subjec t’s follow-up will be required on a weekly basis until the values (transaminases and TBL) 
return to a clinically acceptable level. For the above laboratory blood tests, using the central 
laboratory is recommended. However, if circumstances warrant the use of a local laboratory, 
copies of the local laboratory results will be required. All clinically significant hepatic enzyme 
abnormalities and/or hepatic events are to be documented in the eCRF with prompt submission 
of the adjudication dossier for events that led to study drug discontinuation or were reported as 


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SAEs where no alternative etiology has been found after work-up and where causal relationship 
to study drug cannot be ruled out. 
3. Unplanned cardiac surgery due to aggravation of cardiac conditions; 
4. Pregnancy; 
5. Study terminated by Sponsor; 
6. Protocol violation; 
7. Lack of efficacy. 
Those subjects whose participation extended beyond Month 3 (Visit 5) will have study 
procedures terminated at the time of discontinuation from treatment and study with a 
Discontinuation Visit (Section 6.5.3).  
If the subject discontinued study treatment due to an AE, the Investigator will follow the subject 
until the AE has been clinically stabilized. 
5.6.4. 
Reasons for Withdrawal at any Time during the Study 
Withdrawal of a subject will only occur, by definition, if no additional protocol scheduled visit 
or Follow-Up Visit is possible. The definition of withdrawal is appropriate for those cases that 
occur in the Main Treatment Period because of the requirement to continue subjects on 
scheduled visits even if they discontinue treatment prior to Month 3 (Visit 5). If a subject 
withdraws after Month 3 this would be classified as a discontinuation from treatment and study.  
Any subject who is withdrawn from the study treatment for any reason will have their reasons for 
withdrawal records.  
Subjects may be withdrawn from the study after signing the informed consent form (ICF) during 
the Main Treatment Period for the following reasons: 
 Withdrawal of subject consent by subject or legal guardian(s) 
 Death 
 Lost to follow-up (attempts should be made to not have any subject lost to follow-up) 
 AE that occurs during the Main Treatment Period that requires withdrawal. 
5.6.5. 
Withdrawal Procedures 
If a subject is withdrawn from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of last 
treatment and the reason for withdrawal. Subjects who withdraw from the study during the 3 
month Main Treatment Period will also have a 3 month Follow-Up phone call to ascertain any 
events (TE and/or bleeding events) that may have occurred since withdrawal. The timeframe for 
the 3-month Follow-Up phone call assessment is from the date of subject randomization. 


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5.6.6. 
Procedures for Discontinuation from Treatment or Study; or Withdrawal from 
Study 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has the 
right to discontinue study treatment or withdraw consent for participation in the study at any time 
and for any reason without prejudice to his or her future medical care by the physician or at the 
institution. 
While subjects are encouraged to complete all study evaluations, they may discontinue study 
treatment, discontinue from study, or withdraw from the study at any time and for any reason 
without penalty. Every effort will be made to determine why any subject discontinues study 
treatment, or study, or withdraws from the study prematurely. This information should be 
recorded.  
The most likely reasons for withdrawal are death, lost to follow-up or withdrawal of consent, or 
an AE in which case all subsequent visits will NOT be possible as stated in the protocol.  
All subjects who classify as discontinue from the study treatment or study with an ongoing AE 
must be followed until the event is deemed resolved or clinically stable even if they are not 
willing to participate in the study any longer. If a subject discontinues study or withdraws after 
dosing, all data normally collected prior to study discharge should be collected at the time of 
discontinuation from study or withdrawal, or at the scheduled visit of the study.  
In case of withdrawal, a genuine effort must be made to determine the reason(s) why a subject 
fails to return for the necessary visits. If the subject is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the subject requesting him/her to contact the clinical 
site. 
If a subject is withdrawn or discontinued from study treatment or study, the IXRS will be called 
by the clinical site to register the subject status. 
Please see suggested classification of discontinuation and withdrawal status in Table 5.2. 
Table 5.2: 
Classification of Discontinuation and Withdrawal Status for Subjects by 
Scheduled Visit 
 
Discontinue Treatment 
Discontinue Study 
Withdrawal 
Randomization 
through Month 3 
Eligible 
Not Eligible 
(Need to follow 
through Month 3 with 
Follow-Up Visit) 
Eligible 
(Assumes no additional visit 
is possible, 3-month 
Follow-Up phone call 
attempted from date of 
randomization) 
Beyond Month 3 
through Month 12 
Eligible 
Eligible 
(A Discontinuation 
Study Visit will be 
conducted with 
Follow-Up Visit) 
Not Eligible 
(Unless NO Discontinuation 
Visit is possible, in which 
case a phone call will be 
attempted) 


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5.6.7. 
Follow-Up Procedures. 
Subjects who complete the Main Treatment Period (Month 3) but do not continue into the 
Extension Period, will have a their Month 3 Visit and a Follow-Up Visit 30 days after last dose 
of study drug and discontinued from the study. Follow-Up Visits may be conducted by phone, 
however, if the subject experienced an adverse event of concern (Serious) or an endpoint event 
since their Discontinuation Visit, an office visit is highly recommended. 
Subjects who discontinue treatment from the Main Treatment Period prior to Month 3 will 
continue to be followed monthly according to the Schedule of Events (Appendix 17.1) through 
the Month 3 visit (Visit 5), and have a 30-day Follow-Up Visit. If treatment discontinuation 
occurs prior to Month 2 visit, the 30-day Follow-Up Visit will occur on the same day as the 
Month 3 visit.  
Subjects who extend toward 12 months of study treatment and decide to no longer participate 
will have a subsequent 30-day Follow-Up Visit after their Discontinuation Visit. 
5.6.7.1. 
Temporary Interruption of Study Drug 
If a subject’s treatment with study drug must be interrupted for medical or surgical reasons (eg, 
hospital admission for an invasive procedure, a major medical condition, surgery, 
thrombocytopenia due to cytotoxic medication, or dental work); use of a prohibited concomitant 
medication; or other reasons (eg, temporary situation that prevents subject adherence with the 
study drug administration schedule, etc), the subject’s study drug should be resumed as early as 
the situation allows. Edoxaban should be discontinued for 24 hours prior to the initiation of the 
procedures (depending on PK/PD data in children). Subjects should be encouraged to restart 
study drug after an interruption except when absolutely contraindicated. The duration of study 
drug interruption can vary depending upon the individual circumstances, and study drug may be 
resumed regardless of the duration of time that it had been interrupted. Any subject who 
temporarily interrupts study drug will have the reason recorded in the eCRF. 
5.6.8. 
Subject Re-screening Procedures 
Re-screening (retesting of laboratory test results) is permitted only once for any subject with 
Sponsor approval who failed to meet eligibility criteria upon initial screening related to a specific 
inclusion/exclusion criteria. If a subject needs to be rescreened for any particular time-dependent 
module (ie, laboratory, vital signs, etc.) the Investigator will perform an unscheduled visit within 
30 days of the original screening visit and the appropriate module will be used to accommodate 
new data that would make the subject eligible to be randomized. The subject identification 
number will remain the same at the time of re-screening. The initial screening information and 
the reason why the subject is ineligible for the initial evaluation will be uploaded into the 
electronic data capture (EDC) system.  
Re-screening (re-testing of laboratory results) of a subject may occur only once. If there is a 
failure to meet study entry criteria the failed subject will be recorded in the Screening Log and 
EDC. 


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6. 
STUDY PROCEDURES 
Potential subjects will have the study risks and possible benefits explained, the ICF reviewed, 
and all questions answered for them. Subjects will undergo procedures specific to study 
qualification (Section 6.2) only after the ICF is signed by the subject/or the subject’s legal 
representative, and age appropriate assent obtained from subjects capable of doing so. Subjects 
who complete the screening period and are determined to be eligible for study participation per 
the inclusion and exclusion criteria will be randomized in a 2:1 ratio to either the edoxaban-
treatment arm or the SOC-treatment arm, respectively, for the first 3 months of the study, after 
which all subjects will be offered edoxaban at the appropriate dose for age and weight at the time 
of informed consent  
All subjects will undergo evaluation for safety and efficacy evaluations at the EOT at Month 3 
with a 30-day Follow-Up. Subjects who discontinue treatment prior to Month 3 will continue 
with the scheduled visits up to Month 3 with the 30-day Follow-Up. Subjects who participate in 
the Extension Period will undergo safety and efficacy endpoint evaluations (bleeding events, TE, 
or any other AEs) at Months 6, 9, and 12, and 30-days after cessation of treatment if treatment up 
to 12 months is required. If treatment discontinuation occurs prior to Month 2 visit, the 30-day 
Follow-Up Visit will occur on the same day as the Month 3 visit.  
Subjects will return to the clinical site on a monthly basis to receive study therapy even if there 
are no scheduled procedures. This process will ensure subject compliance and accountability for 
distribution/return of study drug. However, in cases where access to the clinical sites cannot 
occur monthly after Month 3, accommodations will be made to distribute up to 3 months of 
study drug to match the 3-month visit schedule. 
All suspected bleeding and TE endpoints as well as hepatic abnormalities identified by the 
Investigator will be adjudicated by the blinded CEC. Adjudication packages will contain 
appropriate diagnostic tests, clinic notes, laboratory tests, discharge summaries, autopsy reports, 
etc used in the subject work-up following a suspected event.  
6.1. 
Note Concerning Echocardiogram 
All subjects will have an echocardiogram at study screening to rule out asymptomatic 
thrombosis. Subjects with evidence of symptomatic venous or arterial thrombosis during study 
screening period are not permitted in the study. Valid echocardiograms are images taken within 5 
weeks prior to Randomization Visit.  
A follow-up echocardiogram will be taken at Month 3 to ascertain asymptomatic thrombosis. IF 
there is a symptomatic thrombosis prior to Month 3 which would represent a thrombotic event, it 
should be documented by the appropriate imaging procedure. A Month 3 echocardiogram will 
NO LONGER be necessary at Month 3 visit if a symptomatic event was experienced by the 
subject and was documented by an appropriate image. 
In the Extension Period after Month 3, any symptomatic event will be documented and a 
recommended image captured to support the event. The Month 12 echocardiogram will be 
optional in all circumstances. 
A Month 3 echocardiogram is optional if the subject experiences a symptomatic TE documented 
by an image. A reported post-Month 3 symptomatic TE should have a supporting appropriate 


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image. If no symptomatic TE is reported during the Extension Period, the Investigator has the 
option to perform an echocardiogram at his/her discretion to rule out any asymptomatic TE at 
study discontinuation. 
The Schedule of Events for this study is provided in Appendix 17.1.  
6.2. 
Screening/Qualification Visit (At Least Day -30 to Day 1, Visit 1) 
Any protocol-specified study qualification procedures or tests not already done as part of routine 
care will be conducted only after the subject signs the ICF and before randomization.  
Central laboratory specimens will be collected to determine the baseline qualification of the 
subject for inclusion/exclusion criteria and evaluation of particular analytes over time across the 
global study except for INR and aPTT which are performed at the clinical site or local 
laboratory. 
All subjects at the Screening Visit should be assessed for INR and aPTT evaluated at the local 
laboratory.  
Prior to signing the ICF, potential subjects and their parent(s) or guardian(s) will have the study 
risks and benefits explained, the associated ICF and assent form, if applicable, will be reviewed, 
and all questions answered for them. Written informed consent must be signed by the parent(s) 
or guardian(s) of all subjects, and assent obtained from the child, when and where applicable, 
prior to entry into the study.  
 The Screening eCRFs must be completed for every subject with a signed ICF. Any 
protocol-specified study qualification procedures/tests identified for the Screening 
Visit, not already done as part of routine care within 2 weeks of the Screening Visit 
will need to be conducted after the parent(s) or guardian(s) signs the ICF as part of 
the Screening/Qualification Visit.  
 The following study qualification procedures for the Screening/Qualification Visit 
must be completed to ensure that the subject is eligible for the study. 
 Review inclusion/exclusion criteria  
 Record demographic information (date of birth/age, sex, ethnicity, and race) 
 Record medical/surgical history, including: 
 TE history and bleeding history since diagnosis of underlying disease and 
within the past 3 months 
 Date of diagnosis of underlying disease  
 Record prior medication (up to 30 days prior to Screening). Anticoagulant and 
antiplatelet therapy will be captured up to 3 month prior to Screening Visit 
 Assess for and record AEs and concomitant medications. 
 Perform physical examination (Section 9.9) including:  


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 Vital signs (BP, heart rate, and body temperature after resting in a sitting 
or supine position [Note: the appropriate cuff size base on arm 
circumference will be used.])  
 Height and body weight (may be performed by an Investigator or other 
healthcare provider designated by the Investigator).  
 An aPTT and INR assessment will be done for all subjects at Screening at local 
laboratory. Ensure that the subject qualifies with regard to the following central safety 
laboratory and radiology tests for exclusion criteria: 
 Echocardiogram. Note: Valid echocardiograms are images taken within 5 weeks 
prior to Randomization Visit. Note: The presence of a thrombus will disqualify 
the subject from the study. 
 Liver function assessments (ALT, AST, TBL, ALP) (central laboratory) 
 aPTT and INR (assessed locally) 
 Serum chemistry panel, serum creatinine, and eGFR (central laboratory) 
 Hematology (central laboratory) 
 Urinalysis (at central laboratory if dipstick is abnormal) 
Note: Urinalysis can be done at local laboratory. Results of urinalysis performed at Screening by 
local laboratory may be used for qualification 
 To expedite qualification and randomization for subjects living a distance from the 
Investigator site, the site may choose to use their local laboratory for screening 
eligibility labs. The sample should be split with analysis at both the central laboratory 
as well as the local laboratory. For the purpose of eligibility, the local laboratory 
results (aPTT, INR, ALT, TBL, eGFR, and platelet) will be utilized and entered into 
the eCRF. 
If subjects are fulfilling eligibility conditions at the Screening/Qualification Visit, the 
Investigator has the option to randomize the subject at any time within 30 days. The Screening 
Visit and Randomization Visit may occur on the same day. 
6.3. 
Randomization (Day 1, Visit 2)  
Investigators will maintain a confidential subject identification code list of names of all subjects 
randomized to study to allow the Investigator to reveal the identity of any subject when 
necessary. If all procedures and tests done before randomization confirm the subject’s eligibility 
(Section 6.2) for the study, then the IXRS will be contacted to randomize the subject.  
Urine pregnancy test in females of childbearing potential by definition are those females that 
have reached menarche and until becoming postmenopausal unless permanently sterile (defined 
as no menses for 12 months without an alternative medical cause). 
Randomization may occur in IXRS the day prior to dosing for clinical logistics. Screening Visit 
and Randomization Visit may occur on the same day. The first dose of study treatment may 
occur on Day 1 or Day 2 (see Section 5.2.4) 


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The following activities should be done at the time of randomization. 
NOTE: For therapeutic monitoring of SOC the Investigator will use discretion to 
decide when and how often to repeat INR or anti-FXa levels or aPTT measurements 
after randomization. These measurements will be taken and evaluated in the clinic, or 
alternatively, an optional site-specific local laboratory. 
NOTE: For subjects randomized to the edoxaban arm, a blood sample will be 
collected before the first dose of edoxaban for PD analysis only if the subject did not 
receive any heparin (UFH or LMWH) or VKA 24 hours prior to randomization. 
 PD blood sample for subjects randomized to edoxaban taken before dosing that day 
 Discretionary anti-FXa level and/or aPTT measurement for subjects on SOC with 
heparin and INR assessment for the subjects on SOC with VKA 
 Record any prior and/or concomitant medications used since the last visit.  
 Record any AEs since screening visit, including any bleeding events. 
 Urine pregnancy test (for post-menarchal females) 
 Physical examination for body weight only 
 Dispense study drug and record amount (number of tablets/bottles) dispensed. 
Prescription based, locally sourced SOC study therapy will need to be supported by a 
prescription identifying the type of SOC to be provided; 
 Explain the study drugs and the proper daily dosing to the parent(s) or guardian(s) 
and subject (if applicable) using the study drug dosing calendar, and confirm that the 
subject understands the proper daily dosing of study drug. 
 Instruct subject to bring all medications including study drug packaging and bottles to 
each visit (monthly visits even if there are no scheduled procedures). 
 Complete the QOL Questionnaire. Note the QOL can be filled out by EITHER a 
parent or the study participant. The same person should complete the QOL at Month 
3. 
Parent(s) or guardian(s) or legally acceptable representative parent(s) or guardian(s) and subject 
(if applicable) will be provided with information detailing symptoms suggestive of bleeding and 
TE. Parent(s), guardian(s) or subject will be asked to immediately contact the Investigator if 
these symptoms occur.  
The following information may be provided to the parent(s), guardian(s) or subject (information 
booklet): 
 The local medical contact person and emergency telephone number 
 The visit schedule  
 How to recognize and report signs and symptoms of possible bleeding and 
thromboembolic events (see Section 7.1 and Section 9.1).  
 How to use the study drugs and instructions to keep empty medication packages 


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 Blood collections for assessing the INR will be dependent on the discretion of the 
Investigator.  
 Provide subjects with a subject identification safety card and a prohibited medication 
card 
6.4. 
Main Treatment Period 
The Main Treatment Period is defined as the time from randomization until the end of Month 3 
of treatment. All treatment comparative analyses will be made during this time period. 
6.4.1. 
Subjects Randomized to the Edoxaban-Treatment Arm:  
For subjects randomized to the edoxaban arm, a blood sample will be collected before the first 
dose of edoxaban for PD analysis only if the subject did not receive any heparin (UFH or 
LMWH) or VKA 24 hours prior to randomization.  
6.4.2. 
Subjects Randomized to the SOC-Treatment Arm:  
SOC will be provided by the Investigator. Alternatively, local supply depots within each country 
will provide SOC directly to the clinical sites. Subjects will be treated with heparin (UFH or 
LMWH) or VKA according to the site’s SOC treatment procedure. However, if there are 
regulatory or clinical site hurdles providing the SOC, the Sponsor will provide SOC as 
enoxaparin or warfarin (see below).  
If Investigators choose to use the SOC supplied by the Sponsor, the subject will be treated as 
follows: 
 Enoxaparin  Subjects will be treated with enoxaparin alone or as a bridging therapy 
in combination with warfarin during the initial study treatment period. 
 For subjects in whom clinicians prescribe warfarin, this will be started on Day 1. 
Heparin bridging prior to reaching therapeutic levels by INR with warfarin may be 
performed depending on the clinical site’s practice. Bridging therapy will be provided 
by the Investigator for the short duration. The subject will continue warfarin for the 
remainder of the study treatment period.  
The Investigator will use discretion to decide when and how often to repeat INR or anti-FXa 
levels or aPTT measurements. These measurements will be taken in the clinic, or alternatively, 
optional clinical site-specific local laboratory (Appendix 17.1).  
6.4.3. 
Monthly Visits (Months 1 and 2; Visits 3 and 4) for both arms: 
Starting with Randomization, subjects will return to the clinic every 30 days ±5 days (depending 
on the visit, see Schedule of Events in Appendix 17.1) until the Month 3 visit (Visit 5) or study 
withdrawal.  
During study drug interruptions and after study drug discontinuation, subjects will be followed 
for the protocol-specified study procedures to assess the efficacy and safety endpoints and SAEs 
until the Month 3 visit (Visit 5). If a subject discontinues study drug prior to The Main Treatment 


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Period completion, the subject will continue to follow the protocol procedures to Month 3 visit 
and have a 30-day Follow-Up Visit (Visit 9).  
At these monthly on-site visits, discretionary anti-FXa levels assessments and/or aPTT 
measurements will be performed for the subjects on SOC with heparin and INR assessments will 
be performed for the subject on SOC with VKA. Additional interim visits may be scheduled, at 
the Investigator’s discretion, for anti-FXa levels and/or aPTT and INR monitoring. All 
therapeutic monitoring of SOC will be performed locally. 
6.4.3.1. 
Month 1 Visit (Visit 3) Procedures 
The following will be performed at this visit: 
 Record concomitant medications 
 Count unused study drug tablets/bottles/syringe and calculate compliance 
 Dispense study drug medication and review dosing instructions 
 Perform physical examination see Section 9.9 including:  
 Vital signs (BP, heart rate, and body temperature after resting in a sitting or 
supine position [Note: the appropriate cuff size base on arm circumference will be 
used]).  
 Height and body weight (may be performed by an Investigator or other healthcare 
provider designated by the Investigator). 
 Urine pregnancy test in females of child bearing potential. 
 Take blood samples for the following laboratory tests: 
 LFTs (ALT, AST, TBL, and ALP) 
 Serum creatinine and eGFR assessment 
 PK only (pre-dose) 
 PK/ PD blood samples (one time point between 1 and 3 hours post-dose for 
edoxaban-treated subjects) 
 Discretionary anti-FXa level and/or aPTT measurement for subjects on SOC with 
heparin and INR assessment for the subjects on SOC with VKA. 
 Safety review for AEs/SAEs 
 Review for symptomatic endpoint events (bleeding, symptomatic TE with supporting 
imaging) 
6.4.3.2. 
Month 2 (Visit 4) Procedures  
 Record concomitant medications 
 Count unused study drug tablets/bottles/syringe and calculate compliance 
 Dispense study drug medication and review dosing instructions  


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 Perform physical examination (Section 9.9) including:  
 Vital signs (BP, heart rate, and body temperature after resting in a sitting or 
supine position [Note: the appropriate cuff size base on arm circumference will be 
used.])  
 Height and body weight (may be performed by an Investigator or other healthcare 
provider designated by the Investigator) 
 Urine pregnancy test for females of child bearing potential 
 Discretionary anti-FXa level and/or aPTT measurement for subjects on SOC with 
heparin and INR assessment for the subjects on SOC with VKA. 
 Safety review for AEs/SAEs 
 Review for symptomatic endpoint events (bleeding, symptomatic TE with supporting 
imaging) 
6.4.4. 
Month 3 (Visit 5; End of Main Treatment Period) Procedures 
All randomized subjects including those that have discontinued treatment prior to Month 3 will 
have an EOT assessment at Month 3.  
Note: if there was a symptomatic thrombotic event experienced by the subject prior to Month 3 
documented by the appropriate imaging, a Month 3 echocardiogram is not necessary since the 
subject has met an event endpoint. 
The following will be performed at this visit: 
 Perform physical examination (Section 9.9) including:  
 Vital signs (BP, heart rate, and body temperature after resting in a sitting or 
supine position [Note: the appropriate cuff size base on arm circumference will be 
used.])  
 Height and body weight (may be performed by an Investigator or other healthcare 
provider designated by the Investigator).  
 Review concomitant medications  
 Count unused study drug tablets/bottles/syringe and calculate compliance 
 Safety review for AEs/SAEs 
 Review for symptomatic endpoint events (bleeding, symptomatic TE with appropriate 
imaging) 
 Complete the QOL Questionnaire. Note: the QOL can be filled out by EITHER a 
parent or the study participant. The same person should complete the QOL at Month 
3. 
 Take samples for the following: 
 LFTs (ALT, AST, TBL, and ALP) 


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 Serum creatinine and eGFR assessment 
 Hematology 
 Urine pregnancy test (for females of childbearing potential) 
 Discretionary anti-FXa level and/or aPTT measurement for subjects on SOC with 
heparin and INR assessment for the subjects on SOC with VKA 
 At the Investigator’s discretion to extend the study, dispense edoxaban study drug 
medication and review dosing instructions per subject/parent(s)/guardian(s)’s request. 
 Perform echocardiogram to evaluate presence of asymptomatic thrombosis. Note: if 
there was a symptomatic event experience by the subject prior to Month 3 
documented by the appropriate imaging, a Month 3 echocardiogram is not necessary 
since the subject has meet an event endpoint.  
6.5. 
Extension Period (beyond Month 3 – Month 6, 9, and 12; Visits 6, 7, 
and 8) 
At the Investigator’s discretion, study treatment can be extended up to 12 months. All subjects 
will be offered edoxaban treatment for the duration of the Extension Period based on the 
Investigator’s judgment of the subject’s potential thrombotic burden.  
For those subjects switching over from SOC to edoxaban in the extension period, the Principal 
Investigator may use discretion to schedule a visit if necessary and the visit should be 
documented on the designated Unscheduled page in eCRF. 
At any time during the Extension Period, a subject can discontinue treatment and the study. In 
such a case, a discontinuation study visit will be performed with a subsequent 30-day Follow-Up 
Visit (see Table 17.1). 
The subjects on extended treatment will be followed for safety and efficacy assessment including 
bleeding events, TE occurrence, and AEs/SAEs at visit for Months 6 (Visit 6), 9 (Visit 7), and 
12/Discontinuation Visit (Visit 8). Additionally, the subject will have a Follow-Up Visit (Visit 9) 
for safety assessment 30 days after treatment cessation or following Month 12, whichever is first. 
At Month 12/Discontinuation Visit, or at any time the subject discontinues from the study after 
Month 3, the study drug will be collected from the subject and the subject will be switched to 
SOC anticoagulation treatment if necessary, at the discretion of the Investigator. All subjects 
who require continued SOC anticoagulation treatment at the end of study treatment in 
accordance with the current CHEST guidelines will be transitioned to the SOC determined by the 
Investigator. The transition algorithms are provided in Appendix 17.2. The visits will occur 
every 3 months.  
Edoxaban dispensing will occur monthly during the Extended Treatment Period even though 
protocol study procedures have not been scheduled to ensure dosing compliance and drug 
accountability. In cases where clinical visit are not possible every month, a 3-month supply of 
edoxaban may be offered. 


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6.5.1. 
Month 6 (Visit 6) Procedures  
 Record concomitant medications 
 Count unused study drug tablets/bottles to assess compliance 
 Dispense study drug medication and review dosing instructions  
 Perform physical examination (Section 9.9) including:  
 Vital signs (BP, heart rate, and body temperature after resting in a sitting or 
supine position [Note: the appropriate cuff size base on arm circumference will be 
used.])  
 Height and body weight (may be performed by an Investigator or other healthcare 
provider designated by the Investigator).  
 Urine pregnancy test for females of child bearing potential 
 Review for symptomatic endpoint events (bleeding, symptomatic TE with appropriate 
imaging) 
 Safety review for AEs/SAEs 
 Collect blood samples for the following laboratory tests: 
 Serum creatinine test 
 eGFR assessment  
6.5.2. 
Month 9 (Visit 7) Procedures  
 Record concomitant medications 
 Count unused study drug tablets/bottles and calculate compliance 
 Dispense study drug medication and review dosing instructions 
 Perform physical examination (Section 9.9) including:  
 Vital signs (BP, heart rate, and body temperature after resting in a sitting or 
supine position [Note: the appropriate cuff size base on arm circumference will be 
used.]  
 Height and body weight (may be performed by an Investigator or other healthcare 
provider designated by the Investigator).  
 Urine pregnancy test for females of child bearing potential 
 Review for symptomatic endpoint events (bleeding and TE) 
 Safety review for AEs/SAEs 
 Collect blood samples for the following laboratory tests: 
 Serum creatinine 
 eGFR assessment  


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6.5.3. 
Month 12/Discontinuation Visit (Visit 8; Appropriate for subjects completing 
Month 12 or treated beyond Month 3 and discontinuing study prior to Month 
12) 
Discontinuation from study visit will only be required for those extended into the study beyond 
Month 3 because all subjects are to have study procedures through Month 3. 
Procedures for subjects who withdraw consent from the study or are discontinued from the study 
treatment for any reason are discussed in Section 5.6. 
All randomized subjects extended beyond Month 3 who wish to discontinue treatment and study 
will have Discontinuation Visit (Visit 8) performed when the last dose of study drug is 
administered after Month 3.  
The following will be performed at this visit: 
 Record concomitant medications 
 Count unused study drug tablets/bottles and calculate compliance 
 Perform physical examination (Section 9.9) including:  
 Vital signs (BP, heart rate, and body temperature after resting in a sitting or 
supine position [Note: the appropriate cuff size base on arm circumference will be 
used.])  
 Safety review for AEs/SAEs 
 Review for symptomatic endpoint events (bleeding and TE) 
 Collect blood samples for the following laboratory tests: 
 LFTs (ALT, AST, TBL, and ALP) 
 Serum creatinine 
 eGFR assessment 
 Hematology 
 Urine pregnancy test for females of child-bearing potential  
 Optional echocardiogram to evaluate presence of asymptomatic intracardiac 
thrombosis based on Investigator’s discretion. 
6.6. 
Required 30-Day Follow-Up Visit (Visit 9) 
Follow-Up Visits may be conducted by phone, however, if the subject experienced an AE of 
concern (Serious) or a symptomatic endpoint event since the Discontinuation Visit (ie 
symptomatic thrombosis), an office visit is highly recommended. A 30-day Follow-Up Visit will 
be required for all subjects who: 
 Complete the study through Month 3, or 
 Have a discontinuation from study any time after Month 3 prior to Month 12, or  
 Complete Month 12 visit.  


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The following will be recorded or collected at the Follow-Up Visit: 
 AEs/SAEs 
 Review for symptomatic endpoint events (bleeding, symptomatic TE with imaging) 
 Concomitant medications 
6.7. 
Required Month 3 Follow-Up Phone Call for Withdrawal Subject 
Prior to Month 3. 
In the Main Treatment Period a Month 3 Follow-Up phone call will be required for all subjects 
who withdrawal from the study because the assumption is that no additional visit will be 
conducted. The Follow-Up phone call will occur 3 months after the randomization of the subject 
(Month 3). 
The following will be recorded on the Follow-Up phone call: 
 Any symptomatic TE and/or bleeding events during the period of time from 
withdrawal to the phone call Follow-Up. 
 Any AE or serious AE 
 Concomitant medications taken. 


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7. 
EFFICACY ASSESSMENTS 
Details regarding the definitions of the efficacy endpoints and how they will be assessed can be 
found in the CEC charter. The CEC will adjudicate events in a blinded manner. This adjudication 
will be independent of the Investigators. The CEC will complete assessments on an ongoing 
basis, and all information will be recorded in the clinical database.  
Subjects with suspected recurrent TE will undergo objective testing to assess the current episode. 
If possible, a blood sample will be obtained for PD analysis. The following documentation 
should be sent for adjudication: 
 Copies of all diagnostic imaging, 
 The TE adjudication worksheets, 
 eCRFs documents, 
 Source documents including but not limited to hospital discharge summaries, autopsy 
reports, consultation reports, X-rays/scanning reports, and clinical laboratory reports 
7.1. 
Assessments for Efficacy Endpoint(s) 
The efficacy related endpoints are any TE including thrombi in the systemic arterial or venous 
pathways, intracardiac thrombi, DVT, PE, MI, SEE, and stroke which occurred during the study. 
This includes symptomatic TE and/or asymptomatic intracardiac thrombus. 
Diagnosis of TE should be performed per the clinical site’s existing protocol but should include 
at minimum 1 of the following: 
 Asymptomatic intracardiac TE: The presence of an intra-luminal or mural thrombi 
within the cardiac chambers or surgical pathways on any cross-Sectional imaging 
modality. Mild laminar thickening of the internal surface of the Fontan pathway is not 
included. Echocardiography is the preferred modality in this setting.  
 Symptomatic SEE (except stroke) which includes: retinal, upper limb and lower limb, 
mesenteric. 
 The presence of cerebral infarction on computed tomography (CT) or magnetic 
resonance imagining (MRI) (performed after symptoms) 
 The presence of symptomatic pulmonary embolism requires meeting 1 or more of the 
following criteria: 
 An intraluminal filling defect in segmental or more proximal branches of the 
pulmonary artery on multislice CT scan 
 A mismatched defect on a nuclear ventilation/perfusion scan compared to the 
prior imaging, 
 A non-diagnostic lung scan accompanied by documentation of new DVT by 
(Doppler) ultrasonography or venography. 
 Symptomatic DVT requires meeting 1 of the following criteria: 


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 A non-compressible venous segment of the peripheral veins on ultrasonography 
 The presence of an echogenic intra-luminal thrombus or absence of flow in the 
central venous system on Doppler ultrasonography 
 An intraluminal filling defect or venous obstruction on venography 
 An intraluminal filling defect or venous obstruction on CT angiography. 
 An intraluminal filling defect or venous obstruction on MR venography. 
 Death as a result of a thromboembolic event, including pulmonary embolism. All 
deaths will be adjudicated by the CEC.  
 Diagnosis of fatal TE is based on 1 or more of the following: 
 Objective diagnostic testing, 
 Autopsy, 
 Death which cannot be attributed to a documented cause and for which TE 
cannot be ruled out. 
Diagnosis of symptomatic TE requires the confirmation by appropriate diagnostic imaging (see 
imaging criteria of TE) and at least one of the symptoms of TE in the following table: 
Table 7.1: 
Symptoms of Thrombotic Disorders 
Locations 
Symptoms 
Cardiac embolic stroke/ischemic stroke 
 Hemiparesis or focal central nervous system 
deficit 
 Change in mental status (lethargy, 
depressed level of consciousness and coma) 
 Headache 
 Seizures (focal, generalized) 
 Speech disorder, including aphasia and 
mutism 
 Nausea, vomiting 
 Visual impairment (transient obscurations, 
reduced acuity, blindness) 
 Neck pain  
 Fever 
 Respiratory failure (in neonates) 
 Jittery movements (in neonates) 


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Table 7.1: 
Symptoms of Thrombotic Disorders (Continued) 
Locations 
Symptoms 
Intracardiac thrombus 
 Cardiac failure 
 Fatigue 
 Embolic event (Stroke, coronary emboli) 
Myocardial infarction 
 Dyspnea 
 Palpitations 
 Chest pain 
 Pallor 
 Poor feeding 
 Cardiac arrest 
SEE (except Stroke) 
Retinal 
Upper limb and Lower limb 
Mesenteric 
 Vision loss 
 Pain, pallor, paralysis, pulse deficit, 
paresthesia, cold limb, intermittent 
claudication 
 Acute severe abdominal pain, diarrhea, 
vomiting 
VTE in upper limb  
(CVL or non-CVL related) 
 Collateral dilated vein on the chest 
 Superior vena cava syndrome 
 Chylothorax 
 Pain and/or swelling in index limb 
 Reddish or purple discoloration 
VTE in lower extremity 
(CVL or non-CVL related) 
 Reddish or purple discoloration  
 Swelling 
 Pain 
Catheter-related thrombosis 
 Dysfunction of catheter (inability to aspirate 
blood) not attributed to catheter kinking 
 Catheter-sepsis 
 Thrombocytopenia (especially neonates) 


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Table 7.1: 
Symptoms of Thrombotic Disorders (Continued) 
Locations 
Symptoms 
Pulmonary embolism 
 Dyspnea  
 Pain thorax-pleuritic chest pain  
 Hypoxemia-low O2 saturation 
 Hemoptysis 
 Cough 
 Tachycardia 
 Tachypnea,  
 Fever  
 Syncope 
 Right heart failure 
 Cardiopulmonary arrest 
Sinovenous thrombosis 
 Seizures (focal, generalized) 
 Depressed level of consciousness and coma 
 Lethargy 
 Nausea, vomiting 
 Headache 
 Visual impairment (transient obscurations, 
reduced acuity, blindness) 
 Papilledema 
 Hemiparesis 
 Hemisensory loss 
 Ataxia 
 Speech impairment, mutism 
 Cranial nerve palsies  
 Acute psychiatric symptoms 
 Respiratory failure (in neonates) 
 Jittery movements (in neonates) 
 Hydrocephalus 


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Table 7.1: 
Symptoms of Thrombotic Disorders (Continued) 
Locations 
Symptoms 
Splanchnic vein thrombosis 
Portal vein, Splenic vein, Mesenteric vein 
 Abdominal distension/pain 
 Splenomegaly 
 Upper gastrointestinal bleed and/or melena 
with esophageal varices (portal 
hypertension) 
Hepatic vein/vena cava 
 Abdominal distension with ascites and 
hepatomegaly 
 Dilated veins in anterior abdominal walls 
Renal vein thrombosis 
 Palpable flank mass 
 Macro or micro hematuria 
 Thrombocytopenia 
Abbreviations: CVL = central venous line; VTE = venous thromboembolism 
 
Table 7.2: 
Recommended Diagnostic Imaging Methods  
Locations 
Recommended Diagnostic methods 
Cardiac embolic stroke/ischemic stroke 
 Magnetic resonance imaging (MRI) with 
diffusion-weighted imaging  
Alternative Imaging Techniques: 
 Magnetic resonance angiography 
(MRA) 
 Computed tomography 
angiography (CTA) 
In case of suspected cardiac embolic 
stroke, an echocardiogram imaging should 
be performed  
Intracardiac thrombus 
 Echocardiography 
Alternative Imaging Techniques 
 MRI 
 Transesophageal 
echocardiography 


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Table 7.2: 
Recommended Diagnostic Imaging Methods (Continued) 
Locations 
Recommended Diagnostic methods 
Myocardial infarction 
 Echocardiography 
 Angiography  
SEE (except Stroke 
 CTA 
 US/Doppler 
 Echography 
VTE in upper limb  
(CVL or non-CVL related) 
 Ultrasonography (US) for peripheral upper 
limb as axillary, subclavian and jugular 
veins 
Alternative Imaging Techniques: 
 MRI with venography (MRV) for 
central intra-thoracic veins 
 Multi-detector CT venography 
(MDCT venography) 
VTE in lower extremity 
(CVL or non-CVL related) 
 Doppler US (± repeated 1 week) 
Alternative Imaging Techniques: 
 MRV 
Catheter-related thrombosis 
 Doppler US 
 Echocardiography 
Alternative Imaging Techniques: 
 Conventional venography 
 MRV 
Pulmonary embolism 
 V/Q scanning 
 Spiral CT pulmonary angiography (CTPA) 
Alternative Imaging Techniques: 
 Cardiac angiography 
 Conventional pulmonary 
angiography 
 Echocardiography/ 
transesophageal 
 Magnetic resonance pulmonary 
angiography  


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Table 7.2: 
Recommended Diagnostic Imaging Methods (Continued) 
Locations 
Recommended Diagnostic methods 
Sinovenous thrombosis 
 Brain MRI including T2 imaging and MRI 
with venography (MRV) 
Alternative Imaging Techniques: 
 Pre and post-contrast CT scan with 
venography (CTV) 
 Doppler flow US; if fontanelle 
open 
Renal vein thrombosis 
 Doppler/US 
Splanchnic and hepatic veins and vena 
cava  
 Doppler/US 
Alternative Imaging Techniques: 
 CT Scan 
Abbreviations: CT = computed tomography; CTV = CT scan with venography; CVL = central venous line; MDCT 
= Multi-detector CT; MRI = magnetic resonance imaging; MRV = MRI with venography; VTE = venous 
thromboembolism 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) 
The primary and secondary safety and efficacy endpoints respectively, were selected based on 
the current Food and Drug Administration/EMA’s Pediatric Committee (PDCO) guidance on 
anticoagulant indications. The guidance recommends that adjudicated events for bleeds and TEs 
be assessed as outcomes as a consequence of treatment with anticoagulants. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
The timing and handling of blood samples for edoxaban-treated subjects for PK assessments and 
PD biomarkers are defined in Appendix 17.1. Plasma levels of edoxaban and its metabolite, 
D21-2393, will be measured from subjects in the edoxaban-treatment arm. The primary PD 
biomarkers, anti-FXa activity will be assayed from all edoxaban-treated subjects. For all sample 
collections, the study staff will record the date and time of last dose of study drug before sample 
collection and the date and time of the sample collection on the CRF. In addition, for PK 
samples, the date and time of the last meal before sample collection must be recorded onto both 
the eCRF and the laboratory accession form. 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
Up to 3 samples will be collected from subjects in the edoxaban-treatment arm over the course of 
the study for edoxaban and D21-2393 analysis. Samples should be collected tubes with lithium 
heparin as anticoagulant. 
The following blood samples for PK will be collected at Month 1 Visit: 
 1 sample before the dose, 
 1 sample between 1 to 3 hours after the dose at the Month 1 visit, 
 If applicable, 1 sample at an event classified as TE or major or CRNM bleeding 
Note: It is critical to record the date/time of the last dose as well as the date/time of the last meal 
prior to each PK sample collection. Collection information will be guided by the case report 
forms and guidelines. 
8.2. 
Pharmacodynamic (PD) Assessment(s) 
If blood volume restriction allows, blood samples will be collected from edoxaban-treated 
subjects for assessment of PD biomarkers at the following time points: 
 Day 1 (at Randomization): one sample prior to first dose of edoxaban in tubes with 
citrate sodium as anticoagulant  
 Month 1 Visit: one sample between 1 to 3 hours after the edoxaban dose at the Month 
1 Visit at the time of PK specimen 
 If applicable, 1 sample at an event classified as TE or major or CRNM bleeding 
The following biomarkers of coagulation will be determined: PT, aPTT, anti-FXa. 
8.3. 
Biomarker Assessment(s) 
Additional testing from the above of other biomarkers related to coagulation and/or of the 
mechanism of action of edoxaban may be done in the future.  
8.4. 
Immunogenicity 
Not applicable. 


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8.5. 
Pharmacogenomic Analysis 
Not applicable. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
The safety endpoints related to safety objectives are bleeding events, including major, clinical 
relevant non-major and minor bleeding. All potential bleeding events will be adjudicated by an 
independent CEC. Study endpoints and safety data will be periodically reviewed by an IDMC to 
ensure the safety of study participants. 
Bleeding definitions are based on the ISTH modified recommendations1, 
 Major bleeding is defined as a composite (ie, any) of the following: 
 Fatal bleeding; and/or 
 Symptomatic bleeding in a critical area or organ, such as intracranial, intra-spinal, 
intraocular, retroperitoneal, intra-articular, pulmonary, or pericardial, or 
intramuscular with compartment syndrome; and/or 
 Bleeding causing a decrease in hemoglobin level of 2 g/dL (1.24 mmol/L) or 
more, or leading to transfusion of the equivalent of two or more 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 (including interruption or discontinuation of 
study drug). 
 Minor bleeding is defined as any other overt bleeding event that does not meet criteria 
for either major bleeding or clinically relevant, non-major bleeding. 
Minimal criteria defining a significant bleeding per ISTH10 are as follows: 
For each specific bleeding symptom, the ISTH/Scientific and Standardization Committee (SSC) 
joint working group proposed minimal criteria in order to classify a symptom as significant: 
1. Epistaxis:  
 Any nosebleed, especially occurring after puberty that causes subject concern (eg, 
interference or distress with daily or social activities) is considered significant.  
 In general, epistaxis should not be considered significant when it lasts less than 10 
minutes, has a frequency of <5 episodes/year, has a seasonal occurrence, or is 
associated with infections of the upper respiratory tract or other identifiable cause 
(e.g., dusty dry air). 
2. Cutaneous bleeding:  
 Bruises are considered significant when 5 or more (>1 cm) in exposed areas; 


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 Petechiae are considered significant when adequately described by the subject or 
relatives;  
 Hematomas are considered significant when occurring without trauma. 
3. Minor cutaneous wound:  
 Any bleeding episode caused by superficial cuts (eg, by shaving razor, knife, or 
scissors) or that requires frequent bandage changes is considered significant.  
 Insignificant bleeding from wounds includes those of duration <10 minutes and 
lesions that usually require stitches in normal subjects (eg, under the chin).  
 Symptoms should also be manifest on more than 1 occasion to be considered 
significant. 
4. Oral cavity bleeding:  
 Gum bleeding should be considered significant when it causes frankly bloody sputum 
and lasts for 10 minutes or longer on more than one occasion.  
 Tooth eruption or spontaneous tooth loss bleeding should be considered significant 
when it requires assistance or supervision by a physician, or lasts at least 10 minutes 
(bleeding associated with tooth extraction is considered separately).  
 Bleeding occurring after bites to lips, cheek, and tongue should be considered 
significant when it lasts at least 10 minutes or causes a swollen tongue or mouth. 
5. Hematemesis, melena, and hematochezia:  
 Any gastrointestinal bleeding that is not explained by the presence of a specific 
disease should be considered significant. 
6. Hematuria:  
 Only macroscopic hematuria (from red to pale-pink urine) that is not explained by the 
presence of a specific urologic disease should be considered significant. 
7. Tooth extraction:  
 Any bleeding occurring after leaving the dentist’s office and requiring a new, 
unscheduled visit or prolonged bleeding at the dentist’s office causing a delay in the 
procedure or discharge should be considered significant. 
8. Surgical bleeding: 
 Any bleeding judged by the surgeon to be abnormally prolonged, that causes a delay 
in discharge, or requires some supportive treatment is considered significant. 
9. Menorrhagia:  
 Any bleeding that interferes with daily activities such as work, housework, exercise 
or social activities during most menstrual periods should be considered significant.  


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 Criteria for significant bleeding may include any of the following: changing pads 
more frequently than every 2 hours; menstrual bleeding lasting 7 or more days; and 
the presence of clots >1 cm combined with a history of flooding.  
10. Muscle hematomas or hemarthrosis.  
 Any spontaneous joint/muscle bleeding (not related to traumatic injuries) is 
considered significant. 
11. Central nervous system bleeding.  
 Any subdural or intra-cerebral hemorrhage is considered significant 
All safety and efficacy endpoints described will be adjudicated in a blinded manner by the CEC. 
The CEC will require all available details about the bleeding event and related information to 
allow successful objective adjudication of the event. Details may include, but are not limited to, 
information such as the following: 
 Location of the bleeding; 
 Duration of the bleeding; 
 Fatality 
 Treatment for bleeding event, including notes or summary of the recommendations 
from a healthcare professional from whom medical treatment was obtained; 
 Magnitude of the bleeding (including size if skin or subcutaneous hematoma); 
 Hemoglobin levels at randomization and at the time of the bleeding event, lowest 
value, pre- and post-transfusion values, and after resolution of the bleeding event; 
 Diagnostic tests done to evaluate the bleeding such as endoscopy (gastrointestinal 
bleed), ENT consult (ear, nose, throat bleed), urology consult (hematuria or 
urogenital bleeding), surgical consult (skin and soft tissue, including intra-abdominal 
bleeding), gynecological consult (uterine or vaginal bleeding), neurological consult 
(intracranial bleed), or ophthalmology consult (intraocular bleed); 
 Diagnostic scans (CT scans or MRIs), ultrasounds or X-rays performed to evaluate 
the bleeding (intracranial bleed)  
 Any other information that can be of help to the CEC to allow successful objective 
adjudication of the bleeding event. 
9.2. 
Adverse Event Collection and Reporting 
In the event of a medical emergency, the Investigator at the clinical site will institute any medical 
procedures deemed appropriate. A 24-hour Urgent Medical Contact will be provided to contact 
the Medical Monitor for further guidance. 
Sites will receive a contact card where the following numbers (24-hour Urgent Medical Contact) 
are provided: 
 
 (primary number) 
 
(alternative number) 
PPD
PPD


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The medical call center will contact Medical Monitor for the assigned region.  
All AEs (see Section 9.4.1 for definitions) occurring after the subject signs the ICF and up to 30 
days after the last dose of study drug (ie, the Follow-Up Visit), whether observed by the 
Investigator or reported by the subject, will be recorded on the Adverse Event CRF page. 
Medical conditions (including laboratory values/vital signs that are out of range) that were 
diagnosed or known to exist prior to Informed Consent will be recorded as part of medical 
history.  
All AEs, serious adverse events (SAEs), bleeding, and events of special interest are to be 
reported according to the procedures in Section 9.5.  
All laboratory results and vital signs should be appraised by the Investigator to determine their 
clinical significance. Isolated abnormal laboratory results or vital sign findings should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation, lead to dose 
reduction, require corrective treatment, or constitute an AE in the Investigator’s clinical 
judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by evaluating the 
subject. Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit. Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms. The Investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.4. The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature.  
The Investigator must always report the diagnosis as the AE or SAE term. When a diagnosis is 
unavailable, report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available. If the signs and symptoms are 
distinct and do not suggest a common diagnosis, report them as individual entries of AE or SAE.  
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE. Pre-planned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for pre-existing conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 for definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an SAE. 
The Investigator should follow subjects with adverse events until the event has resolved or the 
condition has stabilized. In case of unresolved adverse events, including significant abnormal 
laboratory values at the end of study assessment, these events will be followed until resolution or 
until they become clinically not relevant. 


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9.3. 
Adverse Events of Special Interest 
9.3.1. 
Liver Enzyme Abnormalities/Liver Dysfunction 
Liver function is an area of special interest. Critical liver laboratory assessments include ALT, 
AST, TBL, and ALP. Particular attention will be paid to subjects with ALT and/or AST ≥3 × 
ULN and TBL ≥2 × ULN simultaneously without evidence of cholestasis (ALP ≥2 × ULN is 
considered evidence of possible cholestasis) and without alternative etiology for hepatocellular 
damage.  
Liver enzyme abnormalities that lead to study drug interruption/discontinuation as well will be 
adjudicated in a blinded manner by the CEC. The CEC charter includes a process by which 
selected cases will be adjudicated by a liver disease specialist. 
In cases of liver laboratory abnormalities, it is important to ensure that the nature and the extent 
of liver injury is identified and study subjects are monitored until the liver laboratory 
assessments return to normal. 
If the subject discontinued study drug due to liver enzyme abnormalities, the subject will have 
additional evaluations in order to determine the nature and severity of the liver injury. The 
documents to be sent for adjudication: 
 Results of confirmatory tests and diagnostic evaluation 
 The hepatic event adjudication worksheets. 
If a subject temporarily interrupts (or discontinues) study drug due to confirmed liver enzyme 
abnormalities or jaundice, the subject will have additional evaluations as described in 
Section 5.6.3 at the discretion of the Investigator. 
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the clinical laboratory criteria of a potential Hy’s Law 
case [ALT or AST ≥3 × ULN with simultaneous TBL ≥2 × ULN] should always be reported to 
the Sponsor using a Serious Adverse Events Reporting form, in addition to reporting it in eCRF, 
with the Investigator’s assessment of seriousness, causality, and a detailed narrative. These 
events should be reported within 24 hours of Investigator’s awareness of the event. 
An Independent Data Monitoring Committee (IDMC) may recommend termination of the study. 
Termination may be made for any of the following reasons: 
 Concerns about significantly higher bleeding risk relative to 1 of the study arms, 
 Concerns about drug-induced liver injury, 
 Any other safety concerns based on benefit/risk evaluation by the IDMC. 
If the subject discontinues study drug due to liver enzyme abnormalities, the subject will have 
additional clinical and laboratory evaluations until clinically acceptable resolution in order to 
determine the nature and severity of the potential liver injury. 


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9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product (ICH E2A Guideline. 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 
1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered adverse events. 
9.4.2. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE.  
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 


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9.4.3. 
Severity Assessment 
The following definitions should be used to assess intensity of adverse events: 
 Mild: Awareness of sign or symptom, but easily tolerated, ie, does not interfere with 
subject’s usual function. 
 Moderate: Discomfort enough to cause interference with usual activity. 
 Severe: Incapacitating with inability to work or do usual activity, ie, interferes 
significantly with subject’s usual function. 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event while the 
event itself, however, may be of relatively minor medical significance (such as severe headache). 
This is not the same as "seriousness," which is based on subject/event outcome at the time of the 
event. 
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event and the study drug 
or drugs if a combination is administered on the basis of his/her clinical judgment and the 
following definitions. The causality assessment must be made based on the available information 
and can be updated as new information becomes available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
Or 
 The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
Dose Not Changed: No change in study drug dosage was made. 
Drug Withdrawn: The study drug was permanently stopped. 
Dose Reduced: The dosage of study drug was reduced. 
Drug Interrupted: The study drug was temporarily stopped. 
Dose Increased: The dosage of study drug was increased. 
Not Applicable: (eg, subject died, study treatment had been completed prior to reaction/event, or 
reaction/event occurred prior to start of treatment 


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9.4.6. 
Other Action Taken for Event 
None: No treatment was required. 
Medication required: Prescription and/or over-the-counter medication was required to treat the 
adverse event. 
Hospitalization or prolongation of hospitalization required: Hospitalization was required or 
prolonged due to the AE, whether or not medication was required. 
Other. 
9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the adverse event with no residual effect 
observed. 
 Recovering/Resolving 
 The adverse event improved but has not fully resolved. 
 Not Recovered/Not Resolved 
 The adverse event itself is still present and observable. 
 Recovered/Resolved with Sequelae 
 The residual effects of the adverse event are still present and observable. 
 Include sequelae/residual effects. 
 Fatal 
 Fatal should be used when death is a direct outcome of the adverse event. 
 Unknown 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting – Procedure For Investigators 
All AEs, SAEs, and adverse events of special interest including efficacy and safety endpoints 
that will be adjudicated will be reported in the CRF. 
In the event of a Medical Emergency, the Investigator at the clinical site will institute any 
medical procedures deemed appropriate. A 24-hour Urgent Medical Contact will be provided to 
contact the Medical Monitor for further guidance. 
Sites will receive a contact card where the following numbers (24-hour Urgent Medical Contact) 
are provided: 
 (primary number) 
 (alternative number) 
The medical call center will contact Medical Monitor for the assigned region. 
PPD
PPD


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Fatal or life-threatening serious events that are also efficacy or safety endpoints will be reported 
as an expedited report to the regulatory agencies. Events such as MI, SEE, stroke, VTE, and PE 
and/or safety endpoints such as bleeding events (which are not life-threatening or fatal) will be 
exempted from SAE processing and expedited reporting. Efficacy and safety endpoints will be 
captured on specifically designed eCRFs. These events are clinically anticipated events in the 
target treatment population, and will be periodically reviewed by the IDMC to ensure prompt 
identification of any clinically concerning safety issues. 
The following types of events should be reported by the Investigator on a Serious Adverse Event 
Report form within 24 hours of awareness: 
 SAEs (see Section 9.4.2 for definition), including life-threatening or fatal bleeds. 
 All SAEs resulting in death, regardless of whether they are waived endpoints for 
processing and expedited reporting, will be processed by the CRO for entry into the 
Sponsor's global safety database. 
 Hepatic events meeting combination abnormalities [ALT or AST ≥3 × ULN with 
simultaneous TBL ≥2 × ULN] (potential Hy’s Law case), both serious and non-
serious (see Section 9.3.1 for additional details). 
All events (serious and non-serious, including efficacy and safety endpoint events) must be 
reported with Investigator’s assessment of the event’s seriousness, severity, and causality to the 
study drug. A detailed narrative for SAE or hepatic events meeting the criteria, summarizing the 
course of the event, including its evaluation, treatment, and outcome should be provided. 
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available. Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative. For fatal events, the narrative should state 
whether an autopsy was or will be performed, and include the results if available. Source 
documents (including medical reports) will be retained at the clinical site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
See Section 15.12 for contact information for SAE reporting. Please call your study monitor for 
any questions on SAE reporting.  
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo Inc. and/or CRO will inform Investigators, Institutional Review Boards/Ethics 
Committees (IRBs/ECs), and regulatory authorities of any suspected unexpected serious adverse 
reactions (SUSARs) occurring in other clinical sites or other studies of the study drug, as 
appropriate per local reporting requirements. Daiichi Sankyo Inc. and/or CRO will comply with 
any additional local safety reporting requirements. 


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In the United States, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
study drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to inform the 
IRB per Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
ECs. 
9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo Inc. must be notified of any subject who becomes pregnant while receiving or 
within 30 days of discontinuing the study drug.  
Although pregnancy is not technically an adverse event, all pregnancies must be followed to 
conclusion to determine their outcome. This information is important for both drug safety and 
public health concerns. It is the responsibility of the Investigator, or designee, to report any 
pregnancy in a female subject using the exposure in utero (EIU) reporting form. Please contact 
your study monitor to receive the EIU Reporting Form upon learning of a pregnancy. The 
Investigator should make every effort to follow the subject until completion of the pregnancy and 
complete the EIU Reporting Form with complete pregnancy outcome information, including 
normal delivery and induced abortion. The adverse pregnancy outcome, either serious or non-
serious, should be reported in accordance with study procedures. If the outcome of the pregnancy 
meets the criteria for immediate classification as a SAE (ie, post-partum complications, 
spontaneous or induced abortion, stillbirth, neonatal death, or congenital anomaly, including that 
in an aborted fetus), the Investigator should follow the procedures for reporting SAEs outlined in 
Section 9.5.  
9.8. 
Clinical Laboratory Evaluations 
To expedite qualification and randomization for subjects living a distance from the Investigator 
site, the site may choose to use their local laboratory for screening eligibility labs. The sample 
should be split with analysis at both the central laboratory as well as the local laboratory. For the 
purpose of eligibility, the local laboratory results will be utilized and entered into the eCRF.  
Blood and urine samples (if abnormal by dipstick) for clinical laboratory evaluations will be 
shipped to a central laboratory for analysis. Results of all clinical laboratory tests will be reported 
in the subject’s eCRF or merged electronically with the clinical database.  
9.8.1. 
Hematology  
The ethylenediaminetetraacetic acid tube of blood will be drawn for the hematology assessments 
listed in. These will be measured from samples obtained at the Screening/Qualification visit 
(Visit 1), Month 3 (Visit 5), and Month 12/Discontinuation Visits (Visit 8).  


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Table 9.1: 
Hematology Analyses 
Hemoglobin 
Hematocrit 
Red blood cell (RBC) count (with indices) 
White blood cell (WBC) count  
Platelet count 
9.8.2. 
Blood Chemistry  
A serum separating tube of blood will be drawn for the blood chemistry assessments listed in 
Table 9.2 and performed at the Screening Visit.  
Serum creatinine will also be measured on Month 1, 3, 6, 9, and Month 12/Discontinuation 
Visits.  
Table 9.2: 
Serum Chemistry  
Sodium 
Creatininea 
Potassium 
Blood urea nitrogen 
Bicarbonate  
Alkaline phosphatase  
a Serum creatinine will be measured at Screening and On-Treatment Study Visits (Months 1, 3, 6, 9 and Month 
12/Discontinuation)  
9.8.3. 
Liver Function Test  
The LFT will include alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBL, 
and ALP. The LFT will be measured at Screening and on-treatment study visits at Months 1 
(Visit 3), 3 (Visit 5), and 12 (Visit 8). 
9.8.4. 
Estimated Glomerular Filtration Rate (eGFR) Assessment  
Estimated glomerular filtration rate (eGFR) will be estimated from serum creatinine 
(Appendix 17.9). The eGFR assessment will be done at Screening (Visit 1), Month 1 (Visit 3), 3 
(Visit 5), 6 (Visit 6), 9 (Visit 7), and 12/Discontinuation (Visit 8). Samples taken at the 
Screening Visit should be split to allow for central laboratory analysis and local laboratory 
analysis for qualification. 
9.8.5. 
Urinalysis  
Standard urinalysis using a dipstick will be conducted for all subjects at the Screening 
/Qualification Visit (Visit 1) (Table 9.3). The urinalysis will only be done at Screening (Visit 1). 


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Table 9.3: 
Urinalysis Determinations 
Specific gravity 
Blood 
pH 
RBC 
Protein 
WBC 
Glucose 
Bilirubin 
Ketones 
Urobilinogen 
Abbreviations: RBC = red blood cell; WBC = white blood cell. 
For samples with positive findings on macroscopic analysis (dipstick), urine microscopic 
examination for red blood cells, white blood cells, bacteria, and casts should be performed at the 
central laboratory. 
9.8.6. 
Hepatitis Serology 
If a subject discontinues study drug due to confirmed liver enzyme abnormalities or jaundice, the 
subject will have additional evaluations at the discretion of the Investigator as follows: 
 Hepatitis A, B, C, and E screening (anti-HAV IgM, HBsAg, anti-HCV plus viral titer, 
and evaluation for Hepatitis E),  
 Antinuclear antibody (ANA) and anti-SmAb,  
 Cytomegalovirus (CMV) and Epstein-Barr virus (EBV)  
9.8.7. 
Urine Pregnancy Testing  
All female subjects must have a negative urine pregnancy test at randomization and each of the 
specified visits. A highly sensitive urine pregnancy test will be performed at the Randomization 
Visit (Day 1), On-Treatment Study Visits (Month 1 [Visit 3], Month 2 [Visit 4], Month 3 [Visit 
5], Month 6 [Visit 6], Month 9 [Visit 7] and Month 12 [Visit 8])/ Discontinuation Visit.  
9.8.8 Monitoring of SOC Therapeutic Level 
Routine monitoring of subjects on VKA (INR) or heparin based therapy (Anti-FXa, aPTT) after 
randomization is performed locally and up through Month 3.  
9.9. 
Physical Examination 
Physical examination will be conducted for all scheduled visits except Randomization Visit and 
includes: 
 Height and body weight 
 This may be performed by an Investigator or other healthcare provider designated 
by the Investigator. 
 Vital signs including blood pressure, heart rate, and body temperature after resting in 
a sitting or supine position  
 Note: the appropriate cuff size base on arm circumference will be used. 


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 Vital signs are captured for selected scheduled visits. 
 An assessment of each of the relevant major body systems. 
Information will be entered in the case report form, date of measurement, and measurement 
results for systolic blood pressure, diastolic blood pressure, pulse rate, body temperature, height, 
body weight, and body mass index (BMI). 
9.10. 
Electrocardiograms 
Not applicable. 
9.11. 
Other Examinations 
Not applicable. 


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10. 
OTHER ASSESSMENTS 
A pediatric QOL questionnaire will be issued at randomization and at the end of the treatment 
period (Month 3, Visit 5) to assess such categories as: health and activities, feelings about 
themselves, relationships with others, and school behavior. Note the QOL can be filled out by 
EITHER a parent or the study participant. The same person should complete the QOL at Month 
3. 
PedsQL version 4.0, generic core scale will be used in the study. The Sponsor will provide a hard 
copy of the questionnaire. Data will be entered into the EDC. 
The following questionnaires will be used: 
 Adolescent (13-18) Self report  
 Adolescent (13-18) Parent report 
 Child (8-12) Self report 
 Child (8-12) Parent report 
 Young child (5-7) Self report 
 Young child (5-7) Parent report 
 Toddler (2-4) Parent report 


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11. 
STATISTICAL METHODS 
11.1. 
General Statistical Considerations 
All efficacy analyses will be based on the modified intention-to-treat (mITT) Analysis Set and 
will be performed based on the treatment group assigned at randomization.  
Safety analysis will be performed using the Safety Analysis Set. Subjects will be analyzed 
according to actual treatment received.  
All analyses for the Extension Period will be based on subjects who participate in the Extension 
Period and take only edoxaban in the Extension Period, in the specified analysis set, and will be 
summarized for the edoxaban treatment group. Data listings will be prepared for subjects who 
are randomized to the SOC arm, participate in the Extension Period, and do not switch to 
edoxaban right after the Month 3 Visit. 
All confidence intervals will be descriptive and will be two-sided 95% confidence interval (CI), 
unless otherwise specified. 
Unless otherwise specified, the baseline value of an efficacy variable for a subject is the last non-
missing measurement before the randomization, and the baseline value of a safety variable is the 
last non-missing measurement before the first dose of the study drug. 
In general, missing data will not be imputed for the purpose of data analysis. No visit windows 
will be used for analysis. 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, and minimum and maximum values. Categorical variables will be 
summarized using frequency counts and percentages. Summary statistics will be presented by 
treatment group. 
There is no formal statistical interim analysis planned. However, after the first 50 subjects 
enrolled in the edoxaban treatment group and 25 subjects enrolled in the SOC treatment group 
complete the first 3-month treatment period, an interim assessments by IDMC of safety 
endpoints will be performed to allow for enrollment of subjects <1 year of age into study. 
11.2. 
Analysis Sets 
Randomized Analysis Set will include all subjects who sign the ICF and are randomized.  
Safety Analysis Set will include all subjects in the Randomized Analysis Set who received at 
least 1 dose of study drug. Analysis will be based on the study drug the subject actually received. 
mITT Analysis Set will include all subjects in the Randomized Analysis Set who received at 
least 1 dose of study drug. Analysis will be based on the study drug the subject was randomized 
to receive. 
PK Analysis Set will include all subjects in the Safety Analysis Set who had at least 1 PK sample 
with measurable concentration.  
PD Analysis Set will include all subjects in the Safety Analysis Set who had at least 1 
measurable PD sample.  


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11.3. 
Study Population Data 
Subject disposition will be summarized by treatment group and in total for the Main Treatment 
Period and for the edoxaban treatment group for the Extension Period, respectively, for the 
Randomized Analysis Set. The number and percentage of randomized subjects who discontinued 
treatment prematurely will be tabulated by the main reason for discontinuation by treatment 
group for the Main Treatment Period and for the Extension Period.  
The number of subjects for each defined analysis set will also be tabulated by treatment group as 
well as in total for the Main Treatment Period and for the Extension Period, respectively. 
Subjects excluded from the analysis sets will be listed and summarized by treatment group and 
reason for exclusion for the Main Treatment Period and the Extension Period. A listing of all 
subjects with major protocol deviations will also be provided. 
The demographic and baseline characteristics such as age, sex, race, height, weight, calculated 
BMI, type of underlying disease, taking concomitant aspirin or not at baseline, and primary and 
secondary prevention will be summarized descriptively for the mITT and Safety Analysis Sets. 
The demographic and baseline characteristics will also be summarized for subjects who 
participate in the Extension Period. 
Study drug exposure and study duration will be summarized using descriptive statistics for the 
Safety Analysis Set by treatment group for the Main Treatment Period and the Extension Period. 
Edoxaban compliance will also be summarized using counts of tablets/ bottles. SOC compliance 
will be summarized by Percent time in therapeutic INR range for subjects who receive VKA or 
anti-FXa level for subjects who receive heparin.   
Medical history will be summarized for the Safety Analysis Set. Prior medication will be 
summarized by treatment for the Safety Analysis Set. Concomitant medication will be 
summarized by treatment for the Safety Analysis Set for the Main Treatment Period and for the 
Extension Period. 
11.4. 
Statistical Analysis 
11.4.1. 
Efficacy Analysis 
All confidence intervals will be two-sided 95% confidence intervals, unless stated otherwise. 
11.4.1.1. Secondary Efficacy Analysis  
The TE stated in this Section, include symptomatic thrombi in the systemic arterial or venous 
pathways (DVT, PE, stroke, SEE, intracardiac thrombus, and MI), and asymptomatic 
intracardiac thrombus identified by cardiac imaging.  
The following secondary efficacy endpoints will be summarized by treatment group using 
incidence, and annualized event rate for both the Main Treatment Period and the Extension 
Period, as well the rate difference between edoxaban and the comparator with the corresponding 
95% CI for the Main Treatment Period. The incidence of each component will also be 
summarized by treatment group. This analysis will be based on CEC adjudicated results. 


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 The combination of symptomatic TE in the systemic arterial or venous pathways 
including DVT, PE, stroke, SEE, intracardiac thrombus, MI, and asymptomatic 
intracardiac thrombus identified by cardiac imaging that occur from randomization to 
the Month 3 Visit.  
 Deaths as a result of TE that occurs from randomization to the Month 3 Visit. 
 All-cause mortality occurring from randomization to the Month 3 Visit. 
 The combination of symptomatic TE in the systemic arterial or venous pathways 
including DVT, PE, stroke, SEE, intracardiac thrombus, and MI, and asymptomatic 
intracardiac thrombus identified by cardiac imaging, which occur from the day after 
the Month 3 Visit to the date of last dose of study drug plus 30 days for subjects who 
participate in the Extension Period.  
 Deaths as a result of TE that occurs from the day after the Month 3 Visit to the date of 
last dose of study drug plus 30 days for subjects who participate in the Extension 
Period. 
 All-cause mortality which occur from the day after the Month 3 Visit to the date of 
last dose of study drug plus 30 days for subjects who participate in the Extension 
Period. 
11.4.1.2. Exploratory Efficacy Analysis  
The combination of symptomatic TE and asymptomatic intracardiac thrombus, deaths as a result 
of TE, and all-cause mortality will also be analyzed for periods and subjects below: 
 Events from randomization to the date of last dose of study drug plus 30 days for 
subjects who do not participate in the Extension Period 
 Events from the day after the Month 3 Visit to the data of last dose of study drug for 
subjects who participate in the Extension Period 
 Events occurring from randomization to the Month 3 Visit or to the date of last dose 
of study drug plus 3 days if study treatment is discontinued in the Main Treatment 
Period, whichever is earlier. 
To assess the efficacy for intra-patient between the Main Treatment Period and previous 
anticoagulant regimen, TE history since diagnosis of underlying disease and within the prior 3 
months to randomization will be collected. The incidence of TE and annualized event rate in the 
3 months prior to randomization and during the Main Treatment Period will be calculated for 
subjects who have both pre-randomization and post-randomization data available. This analysis 
will be based on Investigator-reported events. 
To compare edoxaban regimen with available existing historical control data, a literature review 
and a search for registered clinical trials with similar endpoints will be conducted. The available 
results of control data will be extracted and tabulated together with the results of the Main 
Treatment Period from this study.  
TE will also be classified as primary prevention events and secondary prevention events based 
on thrombosis history, and summarized by treatment group for events occurring during the Main 


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Treatment Period and from the day after the Month 3 Visit to the date of last dose of study 
treatment plus 30 days, respectively. Due to the small sample size of the study, further 
stratification by primary and secondary prevention is not feasible. Hence, caution is needed in 
the interpretation of the result, especially when imbalance occurred between two groups. 
11.4.2. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses (Edoxaban Subjects 
Only) 
Plasma concentration and biomarker data will be summarized by age, dose and time point using 
descriptive statistics. The plasma concentration data will be pooled with data from other studies 
for a population PK analysis using nonlinear mixed effects modeling.  
Exposure-response relationships will be evaluated for the safety and efficacy endpoints through a 
model based approach, if data allow, and will be reported separately.  
Pharmacokinetic and pharmacodynamics data will be analyzed separately and reported 
separately. The plasma concentrations of edoxaban and its metabolite, D21-2393, as well as the 
PD measures will be listed and summarized by age, dose and time point. 
11.4.3. 
Safety Analysis 
11.4.3.1. Analysis of Bleeding Events 
The primary safety endpoint is the composite of major and CRNM bleeding events that occur 
during the Main Treatment Period: from the date of first dose of study drug to the Month 3 Visit, 
or to the date of last dose of study drug plus 3 days if study treatment is discontinued, whichever 
is earlier. This analysis will be based on CEC adjudication results. 
The time to major or CRNM bleeding occurring during the Main Treatment Period will be 
compared between treatment groups for subjects in the Safety Analysis Set, using the Cox 
proportional hazards regression model with treatment group, concomitant usage of aspirin at 
baseline, and underlying disease (Kawasaki disease, Fontan surgery, heart failure or Other) as 
covariates. Hazard ratio between edoxaban and SOC treatment group will be calculated with 
corresponding 95% CI. The incidence, annualized event rate, and rate difference between 
edoxaban and SOC treatment groups will also be calculated. 
In addition, incidence, annualized event rate and rate difference between edoxaban and SOC 
treatment groups with corresponding 95% CI will be calculated for following endpoints for 
Safety Analysis Set for the Main Treatment Period. Incidence and annualized event rate will also 
be calculated for the following endpoints occurring from the day after Month 3 Visit to date of 
last dose of study drug plus 30 days in the Extension Period. 
 Major and CRNM bleeding event combined 
 Major bleeding event 
 All bleeding event (major, CRNM, and minor bleeding combined) 
The above 3 categories of bleeding endpoints will also be summarized for the periods and 
subjects below: 


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 Incidence, annualized event rate, and rate difference will be calculated for events 
occurring from the date of first dose of study drug to the date of last dose of study 
drug plus 30 days for subjects who do not participate in the Extension Period. 
 Incidence and annualized event rate will be calculated for events occurring from the 
day after Month 3 Visit to the data of last dose of study drug for subjects who 
participate in the Extension Period. 
To assess the safety for intra-patient between the Main Treatment Period and previous 
anticoagulant regimen, bleeding history since diagnosis of underlying disease and within the past 
3 months of randomization will be collected. The incidence of bleeding events and annualized 
event rate in the 3 months prior to randomization and during the Main Treatment Period will be 
calculated for the subjects who have both pre-randomization and post-randomization data 
available. This analysis will be based on Investigator reported events. 
To compare edoxaban regimen with available existing historical control data for bleeding, a 
literature review and a search for registered clinical trials with similar endpoints will be 
conducted. The available results of control data will be extracted and tabulated together with the 
results of the Main Treatment Period from this study.  
11.4.3.2. Analysis of Hepatic Events 
The analysis of hepatic events will be based on CEC adjudication results. All CEC adjudication 
confirmed hepatic events will be summarized for the characteristics of the hepatic events by 
treatment group for the Main Treatment Period and for the Extension Period. 
11.4.3.3. Adverse Event Analyses 
Treatment-emergent AEs (TEAEs) are defined as AEs that occur, having been absent before the 
study treatment administration, or worsen in severity after the initiation of study treatment 
administration.  
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities. 
The number and percentage of subjects reporting TEAEs will be calculated overall, by system 
organ class, by preferred term, and by treatment group for the Main Treatment Period and for the 
Extension Period. TEAEs will be further summarized by severity and relationship to study drug. 
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs will be 
tabulated, as well as TEAEs leading to discontinuation from study treatments and death events. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, preferred term, system organ class, severity, and relationship to study treatment 
will be provided. Deaths, other SAEs, and other significant AEs, including those leading to 
discontinuation from study treatments, will be listed. 
11.4.3.4. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation and by treatment group for the Safety Analysis Set, as well as for the change from 
baseline for the parameters which planned to collect both at baseline and post-baseline in the 
Main Treatment Period. The baseline value is defined as the last non-missing value before the 


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initial administration of study treatment. In addition, mean change from baseline will be 
presented by treatment group for the maximum and minimum post-treatment values and the 
values at the Month 3 Visit. 
Similar summaries will also be provided for clinical laboratory results by scheduled time of 
evaluation during the Extension Period, as well as for the change from Month 3 Visit to the visits 
after Month 3. 
Abnormal clinical laboratory results will be included a by-subject data listing. 
11.4.3.5. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation and by treatment group for the Safety Analysis Set, as well as for the change from 
baseline in the Main Treatment Period. The baseline value is defined as the last non-missing 
value before the initial administration of study treatment. 
Similar summaries will also be provided for vital signs by scheduled time of evaluation during 
the Extension Period, as well as for the change from Month 3 Visit to the visits after Month 3. 
11.4.4. 
Other Endpoint Analysis 
Descriptive statistics for QOL score at baseline and Month 3 will be summarized for each 
question, each dimension, and overall by treatment group and QOL specified age group for 
Safety Analysis Set. 
11.5. 
Interim Assessment 
No formal statistical interim analysis is planned. However, an interim assessment by the IDMC 
of safety endpoints of the study will take place after the first 50 subjects in the edoxaban 
treatment group and 25 subjects in the SOC arm from 1 to <18 year of age complete the first 3 
months of treatment. This will allow for enrollment of subjects <1 year of age. 
11.6. 
Sample Size Determination 
A sample size of 150 subjects was chosen for this study. This study is not a powered study 
intended to draw conclusions based on statistically significant differences between edoxaban and 
SOC. An adequately powered study would be unachievable due to the significantly large sample 
size required and the enormous challenge to enroll these pediatric patients. Although the sample 
size is not based on statistical consideration, assuming major and CRNM bleeding event rates 
(which are the primary endpoints for this study) are the same as observed in adult Hokusai-VTE 
Study, (ie, 8.5% and 10.3% in edoxaban and SOC arms, respectively); with 100 subjects in 
edoxaban arm and 50 subjects in standard of care arm, the 95% CI around the point estimate of 
the risk difference between edoxaban and SOC is -11.8%, 8.2%.. 
11.7. 
Statistical Analysis Process 
The clinical study will be analyzed by the Sponsor or its agent/CRO. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 


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summarizing other clinical study information such as subject disposition, demographic and 
baseline characteristics, study drug exposure, and prior and concomitant medications. The SAP 
will also include a description of how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock.  
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, 
Cary, NC 27513). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
12.1. 
Monitoring and Inspections 
The Sponsor or designee’s Medical Monitor and regulatory authority inspectors are responsible 
for contacting and visiting the Investigator for the purpose of inspecting the facilities and, upon 
request, inspecting the various records of the study (eg, CRFs, source data, and other pertinent 
documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) and local regulations on the conduct of clinical research will be accomplished through a 
combination of onsite visits by the monitor and review of study data remotely. The frequency of 
the monitoring visit will vary based on the activity at each clinical site. The monitor is 
responsible for inspecting the CRFs and ensuring completeness of the study essential documents. 
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the CRFs. Detailed information is provided in the monitoring 
plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor. Audit of clinical site facilities (eg, pharmacy, drug storage 
areas, laboratories) and review of study related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
The Investigator should respond to audit findings. In the event that a regulatory authority informs 
the Investigator that it intends to conduct an inspection, the Sponsor shall be notified 
immediately. 
12.2. 
Data Collection 
This study employs EDC. The eCRF should be kept current to enable the monitor to review the 
subject’s status throughout the course of the study. The eCRF will be completed, reviewed, and 
electronically signed by the Investigator. Guidelines will be provided to facilitate data entry in 
the EDC modules. 
All written information, study notes, and other material to be used by subjects and investigative 
staff must use vocabulary and language that are clearly understood as source documentation. 


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12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and clinical sites, a Clinical Data 
Management review will be performed on subject data according to specifications given by the 
Sponsor or designee’s. Data will be vetted both electronically and manually for CRFs and the 
data will be electronically vetted by programmed data rules within the application. Queries 
generated by rules and raised by reviewers will be generated within the EDC application. During 
this review, subject data will be checked for consistency, completeness and any apparent 
discrepancies.  
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
SAEs in the clinical database will be reconciled with the safety database. 
All medical history entries (except terms pre-specified on the eCRF) and adverse events will be 
coded using Medical Dictionary for Regulatory Activities. All prior and concomitant 
medications will be coded using World Health Organization Drug Dictionary. 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties. All persons authorized to make entries and/or corrections on 
electronic CRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list. This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s CRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, CRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the clinical site (Trial Master File). Source 
documents include all recordings and observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study. These 
records will be retained in a secure file for the period required by the institution or clinical site 
policy. Prior to transfer or destruction of these records, the Sponsor must be notified in writing 
and be given the opportunity to further store such records. 


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12.5. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities. Essential documents include: 
 Subject files containing completed CRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the IRB/EC and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at clinical 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
All essential documentation will be retained by the institution until told otherwise by the 
Sponsor. 
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator. Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor in writing of the new responsible 
person and/or the new location. 
All Investigators and site personnel must ensure subject confidentiality as outlined in 
Section 15.2. 


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical study 
agreement with the CRO. This agreement will include the financial information agreed upon by 
the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 


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14. 
PUBLICATION POLICY 
 
 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
 European Commission Directive (2001/20/EC Apr 2001) and/or; 
 European Commission Directive (2005/28/EC Apr 2005) and/or; 
 US Food and Drug Administration GCP Regulations: Code of Federal Regulations 
(CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March, 1997 
and/or; 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 of 25 November, 2014; 
 Other applicable local regulations. 
15.2. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained. On the CRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor. Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
15.3. 
Informed Consent  
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent and assent, in writing, from the subject after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered. Subjects should be given the opportunity to ask 
questions and receive satisfactory answers to their inquiries, and should have adequate time to 
decide whether or not to participate in the study. The written ICF should be prepared in the local 
language(s) of the potential subject population. 


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In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the IRB/EC prior to being provided to potential subjects. 
The subject’s written informed consent along with the legal guardian(s) should be documented in 
the subject’s medical records. The ICF should be signed and personally dated by the subject and 
by the person who conducted the informed consent discussion (not necessarily the Investigator). 
The original signed ICF should be retained in accordance with institutional policy, and a copy of 
the signed consent form should be provided to the subject. The date and time (if applicable) that 
informed consent was given should be recorded on the CRF. 
Suggested model text for the ICF and assent for the study and any applicable subparts (genomic, 
PK, etc) are provided in the Sponsor’s ICF template for the Investigator to prepare the 
documents to be used at his or her clinical site. Updates to applicable forms will be 
communicated via letter from the Sponsor. 
For studies in the US, an additional consent is required for the Health Insurance Portability and 
Accountability Act. 
According to 21 CFR 50.55 subpart b it states, “In determining whether children are capable of 
providing assent, the IRB must take into account the ages, maturity, and psychological state of 
the children involved. This judgment may be made for all children involved in clinical 
investigations under a particular protocol, or for each child, as the IRB deems appropriate. In 21 
CFR 50.55 subpart g it states, “When the IRB determines that assent is required, it must also 
determine whether and how assent must be documented”. For this study, the IRB will determine 
the age that is appropriate for the assent. Generally, this age averages at 7 years of age. The IRB 
will also determine the verbiage that may be added, as well as ensure the document is written at a 
level understandable to the population who will be signing the assent. The IRB may also require 
separate assent forms based on the age groups (ie, separate assent forms for subjects 7 to 12 
years and for subjects 13 to 17 years) to ensure the assents maintain their “maturity levels and 
understandability”. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator’s Brochure, any 
subject written instructions to be given to the subject, available safety information, subject 
recruitment procedures (eg, advertisements), information about payments and compensation 
available to the subjects, and documentation evidencing the Investigator’s qualifications should 
be submitted to the EC or IRB for ethical review and approval according to local regulations, 
prior to the study start. The written approval should identify all documents reviewed by name 
and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator must submit and, where necessary, obtain approval from the EC or IRB for all 
subsequent protocol amendments and changes to the ICF. The Investigator should notify the EC 


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or IRB of deviations from the protocol or SAEs occurring at the clinical site and other AE 
reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation, and that 
implementation of changes to the initial protocol and other relevant study documents happen 
only after approval by the relevant regulatory bodies. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.  
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the Investigator becomes aware of. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. Sponsor must be 
notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion criteria, 
dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at least 1 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRBs/ECs of deviations from the protocol in 
accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 
ECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study. The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study.  


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If the subject information is revised, it must be re-approved by the IRB/EC. The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information. The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the Investigator by Daiichi Sankyo Inc. or the CRO. Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all clinical sites in all regions of the 
world. Such amendments will be incorporated into a revised protocol document. Changes made 
by such amendments are documented in a Summary of Changes section in the protocol 
amendment. These protocol amendments will undergo the same review and approval process as 
the original protocol.  
A local protocol amendment will affect study conduct at a particular clinical site(s) and/or in a 
particular region/country. Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 
15.8. 
Study Termination 
The Independent Data Monitoring Committee (IDMC) may recommend termination of the study. 
Termination may be made for any of the following reasons: 
 Concern about significantly higher bleeding risk relative to one of the study arms, 
 Concern about drug-induced liver injury, 
 Any other safety concern based on benefit/risk evaluation. 
The IDMC will alert the Investigator/designee if there are any of the above concerns requiring 
protocol modifications or any other changes in the study. 
The details about the roles and responsibilities of the IDMC and guidelines and rules for 
monitoring the study safety data will be described further in the IDMC charter. 
15.9. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be created to further protect the rights, 
safety, and well-being of subjects who will be participating in this study by monitoring their 
progress and results. The IDMC will comprise of qualified scientists, who are not Investigators 
in the study and not otherwise directly associated with the Sponsor. The IDMC will be described 
in detail in the IDMC Charter. The IDMC will monitor data during the study. All activities of the 
IDMC will be documented. This documentation will include data summaries and analyses 
provided to the committee as well as minutes of the meeting. The IDMC can recommend study 


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or treatment regimen/group termination to a study oversight committee based on pre-specified 
concerns described in the IDMC Charter.  
An independent CRO study statistician will prepare the required data outputs and provide the 
outputs to the IDMC as per the IDMC charter. The statistician will prepare overall summary 
reports for the data including, but not limited to, subject disposition, subject demographics and 
baseline characteristics, subject treatment duration, subjects with bleeding (adjudicated by the 
CEC), subjects with liver enzyme and bilirubin abnormalities, subjects with SAEs, deaths, 
subjects permanently discontinued from study drug due to AEs, and subjects with efficacy 
endpoints such as VTE and cardiovascular mortality, and all-cause mortality etc. 
Further details concerning the IDMC responsibilities, structure, and the frequency of committee 
meetings are elaborated in the IDMC charter. Briefly the IDMC will meet to review the study 
safety data when 10%, 25%, 50%, and 75% of subjects complete Month 3 of any study 
treatment. In addition, the IDMC will review the edoxaban exposure analysis from the U157 
study in addition to the safety data from each age cohort to approve the proposed dose for the 
same age cohort in the U313 study. 
Additionally subjects less than 1 year of age will be admitted to the study after the review by the 
IDMC of safety data of 50% subjects in 1 to <18 years of age group who have completed the 
Main Treatment Period of 3 months (50 subjects in edoxaban arm and 25 subjects in SOC arm). 
15.10. 
Clinical Events Committee 
An independent study specific CEC will review and adjudicate key endpoint events (bleedings, 
all types of TE, stroke, MI, deaths, liver enzyme abnormalities requiring study drug 
discontinuation) without unblinding. Endpoints reported during telephone contacts will also be 
adjudicated.  
The CEC will comprise qualified judges, who are not Investigators in the study and not 
otherwise directly associated with the Sponsor. The CEC judges will remain blinded to treatment 
throughout the adjudication process and the study. The CEC adjudicated data will be used in the 
final efficacy and safety analyses. The CEC and the events and radiologic images it will 
adjudicate will be detailed in the CEC Charter. 
15.11. 
Steering Committee/Executive Committee 
A Study Steering Committee will be created to provide academic and clinical guidance on study 
implementation and conduct of the study, and interpretation of results as specified in the 
Committee Charter. It may consist of Principal Investigator(s), and/or key opinion leaders, as 
well as designated Sponsor and CRO members. 
15.12. 
Address List 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
regularly updated as necessary. 


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15.12.1. 
Sponsor’s Responsible Medical Officer and Clinical Study Leader 
 
Senior Medical Director, Clinical Development, Specialty Medicine  
Daiichi Sankyo Inc. 
211 Mount Airy Road 
Basking Ridge, NJ 07920  
 
15.12.2. 
Sponsor’s Safety Contacts 
  
Senior Director, Clinical Safety and Pharmacovigilance 
Daiichi Sankyo UK Ltd. 
Chiltern Place, Chalfont Park, Gerrards Cross, SL9 0BG • United Kingdom 
 
15.12.3. 
CROs  
IQVIA, Inc. 
5927 South Miami Boulevard 
Morrisville, NC 27560 
Telephone No: 
 
15.12.4. 
EDC Partner 
Chiltern International Inc.  
3147 South 17th Street, Suite 300 
Wilmington, North Carolina 28412  
Telephone No: 
 
15.12.5. 
IXRS Partner 
Suvoda 
181 Washington Street, Suite 100 
Conshohocken, PA 19428 
Telephone No: 
 
  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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15.12.6. 
Central Laboratory Partner 
Q2 Solutions North America (a Quintiles Quest Joint Venture)  
Q2 Solutions  
27027 Tourney Road, Suite 2E  
Valencia, CA 91355 
15.12.7. 
PD Biomarkers 
Medpace Reference Laboratories  
5365 Medpace Way  
Cincinnati, OH 45227 
15.12.9 
PK Samples All Countries 
Q2 Solutions  
19 Brown Road  
Ithaca, NY 14850  
USA  
15.12.10 Sponsor’s Biostatistician 
(Associate Director, Biostatistics, Biostatistics and Data Management) 
Daiichi Sankyo Inc.  
211 Mt. Airy Road 
Basking Ridge, NJ  
Telephone No: 
 
15.12.11 Drug Labeling, Packaging and Distribution  
Fisher Clinical Services Inc. 
7554 Schantz Road 
Allentown, PA 18106 
Telephone No: 
 
PPD
PPD
PPD


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16. 
REFERENCES 
1. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific 
and Standardization Committee of the International Society on Thrombosis and 
Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. J Thromb Haemost 2005; (3)692 4. 
2. Giglia TM, Bulas DI, Sell JE, et al. Thrombotic complications in a pediatric 
cardiovascular surgery population: a nine-year experience [abstract]. J Am Coll Cardiol. 
2001;37:465A. 
3. Manlhiot C, Menjak IB, Brandão LR, et al. Risk, clinical features, and outcomes of 
thrombosis associated with pediatric cardiac surgery. Circulation. 2011;124:1511 1519. 
4. Monagle P, Cochrane A, Roberts R, et al. A multicenter, randomized trial comparing 
heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after 
the Fontan procedure in children. J Am Coll Cardiol. 2011;58(6):645-51. 
5. DU176b Investigator’s Brochure Version 16.0. 13 June 2016. 
6. Young G. Diagnosis and treatment of thrombosis in children: general principles. Pediatr 
Blood Cancer. 2006;46:540 546. 
7. Chalmers EA. Epidemiology of venous thromboembolism in neonates and children. 
Thrombosis Research. 2006;118:3 12. 
8. Nowak-Göttl U, Kosch A, Schlegel N, et al. Thromboembolism in children. Curr Opin 
Hematol. 2002;9:448 453. 
9. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER), Center for Devices and Radiological Health (CDRH). Guidance for 
industry: drug-induced liver injury: premarketing clinical evaluation. (October, 2007). 
Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM072278.pdf.  
10. Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap 
D, ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working 
Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal 
for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8: 
2063 5. 
11. CHEST 2012; 141(2)(Suppl):e737S e801S. 
 


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17. 
APPENDICES 
17.1. 
Schedule of Events 
 


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Table 17.1: 
Schedule of Events  
Study Period 
Screening/ 
Qualification 
Visita 
Randomizationa 
On-Treatment Study Visits 
Required 30-Day 
Follow-Up Visitb 
Main Treatment Period 
Extension Period (Optional) 
Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study Day 
At least Day -30 
to Day 1 
Day 1 
 
Month 1 
Month 2 
Month 3 
Month 6 
Month 9 
Month 12/ 
Discontinuation 
Visitc 
30 Days After 
Last Dose of 
Study Drug or 
Discontinuation 
Visit 
Visit Windowd 
 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
IXRS Transaction 
X 
 
X 
X 
X 
X 
X 
X 
 
IXRS Randomization 
 
X 
 
 
 
 
 
 
 
Study Informed Consent 
X 
 
 
 
 
 
 
 
 
Review Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Record Demographic 
Information 
X 
 
 
 
 
 
 
 
 
Record Medical/Surgical 
History 
X 
 
 
 
 
 
 
 
 
Record Prior and 
Concomitant 
Medications 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
Perform Physical 
Examination (Vital signs 
and Body Height/Weight 
Assessments)f  
X 
 
X 
X 
X 
X 
X 
X 
 
Measure Body Weight 
Only 
 
X 
 
 
 
 
 
 
 
Liver function 
assessment (ALT, AST, 
TBL, ALP)g  
X 
 
X 
 
X 
 
 
X 
 
Serum Creatinine/eGFR 
assessment  
X 
 
X 
 
X 
X 
X 
X 
 
Serum Chemistry Panel 
excluding creatinine 
X 
 
 
 
 
 
 
 
 


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Table 17.1: 
Schedule of Events (Continued) 
Study Period 
Screening/ 
Qualification 
Visita 
Randomizationa 
On-Treatment Study Visits 
Required 30-Day 
Follow-Up Visitb 
Main Treatment Period 
Extension Period (Optional) 
Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study Day 
At least Day 30 
to Day 1 
Day 1 
 
Month 1 
Month 2 
Month 3 
Month 6 
Month 9 
Month 12/ 
Discontinuation 
Visitc 
30 Days After 
Last Dose of 
Study Drug or 
Discontinuation 
Visit 
Visit Windowd 
 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Screening: aPTT, INRh 
Xh 
 
 
Post-randomization: 
INR, Anti-FXa, aPTT, 
Assessment on SOCi 
 
…………………………. X ………………….. 
 
 
 
Echocardiogramj 
X 
 
 
 
X 
 
 
Optional X 
 
Hematology 
X 
 
 
 
X 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
 
X 
……………………………….. X .……………………………………….. 
 
QOL Questionnairel 
 
X 
 
 
X 
 
 
 
 
AE/SAE Reportingm 
………………………………..……………..………………… X ……………………………………………………….…….………… 
Endpoints Reporting 
(Bleeding, TE)n 
……………………………………..…………………………… X …………………………………...…………………………………… 
Study Drug Dispensing 
via IXRS 
 
X 
X 
X 
X 
Dispense on a 
monthly basis after 
Month 3 visit or 
optional 3 month 
distribution of 
edoxaban to match 
visit interval 
 
 
Study Drug Compliance  
 
 
X 
X 
X 
Assess on a monthly basis after Month 3 
visit or at the next scheduled visit if 
3 month drug dispense is used 
 


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Table 17.1: 
Schedule of Events (Continued) 
Study Period 
Screening/ 
Qualification 
Visita 
Randomizationa 
On-Treatment Study Visits 
Required 30-Day 
Follow-Up Visitb 
Main Treatment Period 
Extension Period (Optional) 
Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study Day 
At least Day 30 
to Day 1 
Day 1 
 
Month 1 
Month 2 
Month 3 
Month 6 
Month 9 
Month 12/ 
Discontinuation 
Visitc 
30 Days After 
Last Dose of 
Study Drug or 
Discontinuation 
Visit 
Visit Windowd 
 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
PK Samplingo 
 
 
X 
 
 
 
 
 
 
PD Samplingp 
 
Xp 
X 
 
 
 
 
 
 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; aPTT = activated partial thromboplastin time; AST = aspartate 
transaminase; CRNM = clinically relevant non-major; eCRF = electronic case report form; FXa = activated Factor X; INR = international normalized ratio; 
IXRS = Interactive Web/Voice Response System; LIFT = liver function test; LMWH = low molecular weight heparin; PD = pharmacodynamics; 
PK = pharmacokinetics; QOL = Quality of Life; SAE = serious adverse event; SOC= standard of care; TBL = total bilirubin; TE = thromboembolic events; 
UFH = unfractionated heparin; ULN = upper limit of normal; VKA = vitamin K antagonist.  
a Randomization may occur in IXRS the day prior to dosing for clinical logistics. Screening and Randomization may occur on the same day. The site may choose 
to use their local laboratory for screening eligibility labs. The sample should be split with analysis at both the central laboratory as well as the local laboratory. 
For the purpose of eligibility, the local laboratory results will be utilized and entered into the eCRF.  
b Follow-Up Visit will be performed 1 month after the subject completes the study (Month 3 or Month 12) or 30 days after discontinuation from study in the 
Extension Period. If discontinuation occurs prior to Month 2 visit, Month 3 visit will be combined with 30-day Follow-Up Visit. Follow-Up Visits may be 
conducted by phone, however, if the subject experienced an adverse event of concern (Serious) or a symptomatic endpoint event since their Discontinuation 
Visit, an office visit is highly recommended. 
c If a subject completes the Main Treatment Period and discontinues from the study after Month 3 but prior to Month 12, a study visit is required at that time and 
will be referred to as the Discontinuation Visit. 
d Scheduling of visits within windows should be done with caution to the drug supply available in a dispensing unit. Randomization may be performed the same 
day as the Screening/Qualification Visit.  
e Prior medications include 30 days prior to Screening/Qualification Visit. Record anticoagulant and/or antiplatelet therapy up to 3 months prior to Screening 
Visit. 
f Targeted physical examination performed by an Investigator or other healthcare professional designated by the Investigator. Vital signs include blood pressure, 
heart rate, and body temperature after resting in a sitting or supine position [Note: the appropriate cuff size base on arm circumference will be used.] see 
Section 9.9). Height and body weight (may be performed by an Investigator or other healthcare provider designated by the Investigator).  
g Hepatitis serology will be performed if a combination of LFT and TBL abnormalities which define Hy’s Law cases as ALT and/or AST ≥3 × ULN with TBL 
≥2 × ULN. 
h aPTT and INR assessment will be done for all subjects at local laboratory.  


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i Discretionary anti-FXa levels assessments and/or aPTT measurements will be performed locally for the subjects on SOC with heparin (UFH or LMWH) and 
INR assessments will be performed locally for the subject on SOC with VKA. Additional interim unscheduled visits may be performed at the Investigator’s 
discretion to assess VKA therapeutic levels (2-3) based on INR and to assess LMWH or UFH therapeutic blood levels based anti-FXa activity (and/or) aPTT.  
j Note: Valid screening echocardiograms are images taken within 5 weeks prior to Randomization Visit. A Month 3 echocardiogram is optional if the subject 
experiences a symptomatic TE documented by an image. A reported post-Month 3 symptomatic TE should have a supporting appropriate image. If no 
symptomatic TE is reported during the Extension Period, the Investigator has the option to perform an echocardiogram at his/her discretion to rule out any 
asymptomatic TE event at study discontinuation.  
k Highly sensitive urine pregnancy test to be performed for females of childbearing potential.  
l Only the parent or study participant will fill out the form. The same person will fill out the QOL questionnaire at the Screening Visit and Month 3.  
m AE/SAE reporting should occur throughout the study and not be restricted to specific visits.  
n Symptomatic endpoint events should be reported as soon as site personnel learn of the event. Symptomatic endpoint event surveillance with supporting imaging 
should occur throughout the study and not be restricted to specific visits.  
o Only for subjects receiving edoxaban. In addition, one sample will be taken at for every AE classified as a TE, or major or CRNM bleeding. PK samples will 
be collected pre-dose and 1 to 3 hours post-dose.  
p At Day 1, Visit 2 (at Randomization), one PD sample will be collected prior to first dose of edoxaban in tubes with citrate sodium as anticoagulant and at 
Month 1 Visit 3, one sample will be collected between 1 to 3 hours after the edoxaban dose at the same time of PK specimen. For subjects randomized to the 
edoxaban arm, a PD blood sample will be collected only if the subject did not receive any heparin (UFH or LMWH) or VKA within a 24-hour wash-out period 
prior to randomization. 
 


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17.2. 
Recommendations per CHEST 2012 Guidelines11  
Table 17.2 shows the initial treatment and prophylactic doses of LMWH that are used in 
pediatric subjects based on age.  
Table 17.2: 
Doses of LMWH (enoxaparin) Used in Pediatric Subjects 
Drug 
Age 
Initial Treatment Dose 
Initial Prophylactic Dose 
 Age–Dependent Dose 
of Enoxaparin 
<2 months 
1.5 mg/kg/dose q12h 
0.75 mg/kg/dose q12h 
>2 months 
1.0 mg/kg/dose q12h 
0.5 mg/kg/dose q 12h 
Enoxaparin has 110 anti-Factor Xa units/mg 
Recommended target anti-FXa range for LMWH is 0.5 to 1.0 IU/mL.  
Note: The anti-FXa assay detects heparin in subject’s plasma based on 
inhibition of Factor Xa in the assay reagent. 
 
Table 17.3 shows the protocol for anticoagulation therapy to maintain an INR between 2 and 3 
for pediatric subjects on warfarin therapy.  
Table 17.3: 
Protocol for Anticoagulation Therapy to Maintain an INR Between 2 and 3 
for Pediatric Subjects (Warfarin Treatment) 
1 
Day 1: if the baseline INR is 1.0 to 1.3: Dose 0.2 mg/kg orally 
 
2 
Loading 0.2 mg/kg Days 2-4: if the INR is: 
 
INR 
Action 
 
1.1 – 1.3 
Repeat initial loading dose 
 
1.4 – 1.9 
50% of initial loading dose 
 
2.0 – 3.0 
50% of initial loading dose 
 
3.1 – 3.5 
25% of initial loading dose 
 
>3.5 
Hold until INR <3.5; then restart at 50% 
decreased dose 
 
3 
Maintenance oral anticoagulation dose guidelines: 
 
INR 
Action 
 
1.1 -1.4 
Increase by 20% of dose 
 
1.5 – 1.9 
Increase by 10% of dose 
 
2.0 – 3.0 
No change 
 
3.1- 3.5 
Decrease by 10% of dose 
 
>3.5 
Hold until INR <3.5; then restart at 20% 
decreased dose 
Abbreviations: INR = international normalized ratio 


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17.3. 
Effective Methods of Birth Control  
Women of childbearing age are defined as those females that have reached menarche and until 
becoming postmenopausal unless permanently sterile (defined as no menses for 12 months 
without an alternative medical cause) and are eligible for the study based on the inclusion and 
exclusion criteria. 
Female subjects of childbearing potential must test negative for pregnancy at Randomization 
(with a highly sensitive test) and must consent to avoid becoming pregnant by using an approved 
contraception method throughout the study.  
The following use of reliable method(s) of contraception, and/or abstinence, for the duration of 
therapeutic product exposure is recommended:  
Highly effective methods of contraception, when used consistently and correctly, result in 
low failure rates. These may include:  
 Combined (estrogen and progesterone-containing) hormonal contraception associated 
with inhibition of ovulation 
 Oral 
 Intravaginal 
 Transdermal 
 Progresterone-only hormonal contraception associated with inhibition of ovulation 
 Oral 
 Injectable  
 Implantable 
 Intrauterine device (IUD) 
 Intrauterine hormonal-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Sexual abstinence 
Effective methods may include:  
 Barrier methods of contraception (eg, male condom, female condom, cervical cap, 
diaphragm, contraceptive sponge).  
Note: When used consistently and correctly, "double barrier" methods of 
contraception (eg, male condom with diaphragm, male condom with cervical cap) 
can be used as an effective alternative to the highly effective contraception 
methods described above.  
Only in individual cases where the stable use of highly effective methods is medically 
contraindicated (investigator’s written documentation required), double barrier methods may be 
acceptable.  


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Oral contraception is not contraindicated with edoxaban but maybe not recommended in patients 
with high risk of thromboembolic events. The use of oral contraception is per Investigator’s 
discretion. 
17.4. 
Contraindications for Standard of Care Therapy 
Contraindications to warfarin (COUMADIN): 
 Hypersensitivity to the active substance or to any of the excipients 
 Hemorrhagic stroke 
 Clinically significant bleeding 
 Use within 72 hours of major surgery with risk of severe bleeding  
 Use within 48 hours postpartum 
 Pregnancy  
 Drugs where interactions may lead to a significantly increased risk of bleeding 
Contraindications to enoxaparin (LOVENOX): 
 Hypersensitivity to either enoxaparin sodium, heparin or its derivatives including 
other LMWH 
 Acute bacterial endocarditis 
 Active major bleeding 
 Conditions with a high risk of uncontrolled hemorrhage, including recent 
hemorrhagic stroke or thrombocytopenia in subjects with a positive in-vitro 
aggregation test in the presence of enoxaparin; active gastric or duodenal ulceration 
 Subjects receiving heparin for treatment rather than prophylaxis 
Note: Loco-regional anesthesia in elective surgical procedures is contraindicated. 
Contraindications to UFH:  
 History of heparin-induced thrombocytopenia (with or without thrombosis)  
 Uncontrolled, active bleeding (except disseminated intravascular coagulation) 
 Acute bacterial endocarditis 
 When suitable, blood-coagulation tests (eg, the whole-blood clotting time, partial 
thromboplastin time, etc) cannot be performed at appropriate intervals 
 Hypersensitivity to heparin 
 Advanced renal or hepatic dysfunction 
 Severe hypertension 
 Major surgery involving the brain, spinal cord and eye. 


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17.5. 
Prohibited Concomitant Medications at Any Time during the 
Treatment Period with Edoxaban or SOC 
The list here (in the protocol) is static and reflects the list at the time of the current version of the 
protocol. If there are changes to this list during the study, the changes will not be considered a 
protocol amendment and the list in this appendix will not be updated unless the protocol is being 
amended for other reasons as well.  
Subjects on these drugs at the time of planned randomization will be excluded from the study. 
After randomization, use of these drugs will require a study drug permanent discontinuation 
unless advised otherwise in the Sections below. The Investigator is encouraged to contact the 
Medical Monitor for further guidance. 
Sites will receive a contact card where the following numbers (24-hour Urgent Medical Contact) 
are provided: 
 (primary number) 
 (alternative number) 
17.5.1. 
Antiplatelet Drugs 
Use of any antiplatelet medication as single or dual agent antiplatelet therapy is prohibited while 
on study drug except for low dose aspirin defined as 1 to 5 mg/kg/day with maximum of 100 
mg/day. If there is a clinical indication for single or dual agent antiplatelet therapy, the subject 
will need to be discontinued from the study treatment. 
Examples of non-aspirin oral antiplatelet agents include the following: 
 Thienopyridines: clopidogrel (Plavix®), ticlopidine (Ticlid®), prasugrel (Effient®) 
 Dipyridamole: Persantine®, Aggrenox® 
 Cilostazol (Pletal®) 
 Pentoxifylline (Trental®) 
 Sulfinpyrazone (Anturane®) 
 Ticagrelor (Brillanta®) 
IV antiplatelet agents include the following: 
 Glycoprotein IIb/IIIa inhibitors: Abciximab (ReoPro™), Eptifibatide (Integrilin®), 
 Tirofiban (Aggrastat®) 
 P2Y12 Inhibitor: Cangrelor 
 Dextran 
17.5.2. 
Oral Anticoagulants Other than Study Drug 
Oral anticoagulants including Factor IIa inhibitors (eg, dabigatran), and FXa inhibitors (eg, 
rivaroxaban, apixaban) are prohibited in both treatment arms. The only allowed oral 
anticoagulants are the study drugs. 
PPD
PPD


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17.5.3. 
Parenteral Anticoagulants 
Parenteral anticoagulants are prohibited in the edoxaban-treatment arm. Direct thrombin 
inhibitors are prohibited in both the edoxaban arm and in the SOC arm.  
Examples of prohibited parenteral anticoagulant medications include the following: 
 LMWH: enoxaparin (Lovenox®, Clexane®), dalteparin (Fragmin®), tinzaparin 
(Innohep®, Logiparin®), reviparin (Clivarin®), nadroparin (Fraxiparine®), ardeparin 
(Normiflo®), certoparin (Sandoparin®), parnaparin (Fluxum®) 
 UFH: Calciparine®  
 Direct thrombin inhibitors: bivalirudin (Angiomax®), argatroban, (Acova®), 
desirudin (Iprivask®), lepirudin (Refludan®) 
 FXa inhibitors: fondaparinux (Arixtra®)  
17.5.4. 
Intravenous Fibrinolytics 
Intravenous fibrinolytics are prohibited in both treatment arms. Examples of fibrinolytics include 
the following: 
 Tissue plasminogen activator (tPA, alteplase, Activase®), 
 TNK (tenecteplase, TNKase®), 
 rPA (reteplase, Retavase®), 
 Streptokinase (Streptase®), 
 Anistreplase (Eminase®). 
If a subject requires treatment with a fibrinolytic agent, then study drug must be discontinued. 
17.5.5. 
Non-Steroidal Anti-Inflammatory Drugs (excluding aspirin) 
While on study drug, NSAIDs cannot be taken for ≥4 days per week. Less frequent use of 
NSAIDs is permitted while on study drug. However, the Investigator should weigh the 
benefit/risk of NSAID use in combination with an oral anticoagulant for the individual subject. 
Table 17.4 lists examples of NSAIDs. 


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Table 17.4: 
Thorough List of NSAIDs 
Aceclofenac  
Amtolmetin  
Bromfenac 
Clonixin 
Diclofenac 
Dipyrone 
Etofenamate 
Fenoprofen 
Flufenamic Acid 
Ibuprofen 
Isoxicam 
Lansoprazole/Naproxen 
Meclofenamate 
Morniflumate 
Niflumic Acid 
Oxycodone/Ibuprofen 
Pirazolac 
Prophenazone 
Suprofen 
Tiaprofenic Acid 
Acemetacin  
Azapropazone  
Bufexamac  
Dexibuprofen  
Diclofenac/Hyaluronic Acid  
Droxicam  
Felbinac  
Fentiazac  
Flurbiprofen or Fluribuprofen 
Indomethacin  
Ketoprofen  
Lornoxicam  
Mefenamic Acid  
Nabumetone  
Nimesulide  
Phenylbutazone  
Piroxicam  
Proquazone  
Tenidap  
Tolmetin  
Alclofenac 
Benoxaprofen 
Carprofen  
Dexketoprofen 
Diflunisal 
Etodolac 
Fenbufen 
Floctafenine 
Hydrocodone/Ibuprofen 
Indoprofen  
Ketorolac  
Loxoprofen  
Meloxicam  
Naproxen  
Oxaprozin  
Piketoprofen  
Pirprofen  
Sulindac  
Tenoxicam  
Zomepirac 
17.5.6. 
P-gp Inducers (Prohibited Medication) 
Rifampin is a P-gp inducer that has been shown to lower the edoxaban exposure  Therefore, 
concomitant use of rifampin is contraindicated during the treatment period. Other P-gp induces 
may lead to a lower exposure of edoxaban than predicted for clinical efficacy. The example 
medications listed below (but not limited to) have not been tested with edoxaban but are also P-
gp inducers. These should be avoided during the study as their use may lead to a lower exposure 
of edoxaban than predicted for clinical efficacy. (http://www.straighthealthcare.com/p-
glycoprotein.html#inducers). 
 Rifampin 
 Carbamazepine (Tegretol®)  


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17.6. 
Concomitant Medications that Require Edoxaban Dose Adjustment 
17.6.1. 
P-gp Inhibitors List 
Use of P-gp inhibitors during the treatment with edoxaban will require dose reduction either at 
randomization or during the course of the study. These drugs can potentially raise the exposure 
level of edoxaban. The only exemption from this rule is the use of amiodarone which will not 
require dose reduction. 
Table 17.5 shows examples (not limited to) of the most commonly used P-gp inhibitors: 
Table 17.5: 
P-gp Inhibitors List 
Drug Class 
Drug Name 
Antiarrhythmics 
Amiodarone, quinidine, verapamil, dronedarone, carvedilol, 
ranolazine. 
Antibiotics 
Clarithromycin. 
Anti-fungal 
Itraconazole 
Others 
Lapatinib, lopinavir, ritonavir, propafen 
 


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17.7. 
Transition From Edoxaban to Other Anticoagulants 
Subjects who require anticoagulation at the end of study participation will be transitioned to 
standard-of-care treatment as directed by the Investigator or treating physician.  
At the end of edoxaban treatment, the subject will receive the last dose of edoxaban and all 
remaining edoxaban tablets/bottles will be collected from the subject by site staff.  
Subjects transitioning from edoxaban to any VKA will have their INR recorded at last study 
visit. Bridging with heparin may occur during VKA titration until the INR is at a therapeutic 
level of 2 to 3. 
INR will need to be measured as frequently as necessary until the INR target of ≥2. Once the 
INR is ≥2.0 the heparin will be stopped and the subject will continue on the VKA alone. 
When transitioning from edoxaban to another direct oral anticoagulant (e.g. rivaroxaban, 
apixaban, dabigatran): 
 The first dose of the direct oral anticoagulant of choice will be given 24 hours post 
the last dose of edoxaban and will then be continued as per the novel anticoagulant’s 
label. 
For subjects who do not complete the Main Treatment Period, they will be followed with 
monthly visits until the end of Month 3 and have a 30-day Follow-Up Visit according to the 
Schedule of Events (Appendix 17.1).  
For subjects who complete the Main Treatment Period but do not continue into the Extension 
Treatment Period, the subjects will receive a Discontinuation Visit and a Follow-Up Visit, 30 
days after last dose of study drug. 
For subjects who continue into the Extension Period, the Follow-Up Visit will occur 30 days 
after the Discontinuation Visit (Month 12, Visit 8). 


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17.8. 
Management of Serious/Life-Threatening Bleeding 
The following steps are currently recommended for subjects with ongoing major bleeding (see 
Section 9.1): 
 Withhold study drug and all antiplatelets/anticoagulants  
 Institute SOC for major bleeding (large bore IV or central venous line, type and 
crossmatch blood, admit to the intensive care unit, provide hemodynamic and 
respiratory support) 
 Administer packed red blood cells (or whole blood) as needed 
 Administer antidotes if applicable 
For UFH/LMWH:  
The antidote for UFH/LMWH is protamine sulfate. The dose of protamine sulfate given is 
dependent upon the dose of UFH/LMWH administered and the time of administration.  
Suggestions from the Sponsor: 
 If protamine is given within 8 hours of the UFH/LMWH then a maximum 
neutralizing dose is 1 mg protamine/100 units (or 1 mg) of UFH/LMWH given in the 
last dose. 
 If more than 8 hours have passed since the dose of UFH/LMWH was given, 
administer 0.5 mg protamine per 1 mg (100 units) of UFH/LMWH given.  
Protamine is administered by slow IV infusion (over 10 minutes) to avoid a hypotensive 
reaction. Protamine is a medication that requires a high level of caution when being prescribed 
and administered. Outside cardiac surgery and intensive care unit (ICU), consultant or fellow 
approval is required for the use of protamine- do not allow this to lead to delayed administration 
in the case of bleeding. Contact the appropriate senior person immediately. 
For Warfarin: 
If a subject has significant but not life-threatening bleeding: Administer Vitamin K 0.5 mg to 2 
mg SC (NOT intramuscularly) plus fresh frozen plasma (20 mL/kg IV) to a maximum of 4 units. 
If a subject has major bleeding (any INR) or requires emergency surgery doses because their 
INR >8:  
 Stop Warfarin 
 Vitamin K (30 µg/kg) IV, consider higher doses if INR >8 
 Prothrombin complex concentrate (PCC) replacement therapy (To note: fresh frozen 
plasma gives inferior correction and is not recommended): 
 Beriplex® [4-factor Prothrombin Complex Concentrate approved in several 
European countries] (and Kcentra® approved in the United States) (Discuss with 
on call hematologist). Beriplex dosage is calculated based on the current INR and 
subject’s weight (see Table 17.6) 
 Repeat the INR following PCC 


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 Further doses of Beriplex or Vitamin K may be required 
Table 17.6: 
Dose Adjustments for INR Elevation 
INR 
Approximate Dose 
2.0-3.9 
1 mL/kg = 25 IU/kg 
4.0-6.0 
1.4 mL/kg = 35 IU/kg 
>6.0 
2 mL/kg = 50 IU/kg 
For Edoxaban:  
Although not evaluated in clinical trials, PCC, activated PCC, or recombinant Factor VIIa could 
be considered for the reversal of the anticoagulant effect of edoxaban. In healthy volunteers, a 3-
factor PCC restored thrombin generation (area under the curve for thrombin generation curve) 
but did not normalize PT. Thus, a 3-factor PCC may be of some value in reversing anticoagulant 
effects of edoxaban (Study A-U150). 
A specific reversal agent for edoxaban is not available. Although not evaluated in subjects, PCC 
(Beriplex® or Kcentra®), activated PCC, or recombinant Factor VIIa could be considered for the 
reversal of the anticoagulant effect of edoxaban. 
The following are not expected to reverse the anticoagulant effects of edoxaban: 
 Protamine sulfate, 
 Vitamin K, 
 Tranexamic acid. 
Hemodialysis does not significantly contribute to edoxaban clearance.  
In the event of a Medical Emergency, the Investigator at the clinical site will institute any 
medical procedures deemed appropriate. A 24-hour Urgent Medical Contact will be provided to 
contact the Medical Monitor for further guidance. 
Sites will receive a contact card where the following numbers (24-hour Urgent Medical Contact) 
are provided: 
(primary number) 
 (alternative number) 
The medical call center will contact Medical Monitor for the assigned region. 
PPD
PPD


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17.9. 
Estimated Glomerular Filtration Rate (eGFR) Assessment 
Table 17.7 shows the estimated glomerular filtration rate assessment, including the eGFR 
threshold for dose reduction.  
Table 17.7: 
Estimated Glomerular Filtration Rate Based on Age 
Age (Sex) 
Normal eGFR 
 
(Mean eGFR±SD) 
30% Minimal eGFR for 
Study 
Qualificationa 
 
(Mean eGFR by 
Formula)  
eGFR Threshold for 
Dose Reductionb 
 
(Mean eGFR by 
Formula)  
1 week 
(males and females) 
41 ± 15 
10 
15 
2-8 weeks 
(males and females) 
66 ± 25 
10 
20 
>8 weeks 
(males and females) 
96 ± 22 
20 
35 
2-12 years 
(males and females) 
133 ± 27 
30 
50 
13-21 years 
(males) 
140 ± 30 
35 
55 
13-21 years 
(females) 
126 ± 22 
30 
50 
eGFR: estimated glomerular filtration rate; m; meters; min: minutes; mL: milliliter; SD: standard 
deviation 
Ref: American Journal of Kidney Diseases, Vol 39, No 2, Suppl 1 (February), 2002: S46-S75 
a Subject may be enrolled if eGFR is at or greater to this value as determined by the age appropriate formula 
indicated below: 
b eGFR must be less than this value for dose reduction (which corresponds to approximately ≤50% eGFR). 
Modified Schwartz equation (pediatric subjects < 12 years of age):  
CrCl (mL/min/1.73 m2) = (K * Ht) / Scr  
 height (Ht) in cm; serum creatinine (Scr) in mg/dL   
 K (proportionality constant): 656  
Infant (LBW < 1year): K=0.33  
Infant (Term <1year): K=0.45  
Female Child (<12 years): K=0.55 
Male Child (<12 years): K=0.70   
Cockcroft-Gault equation (pediatric subjects ≥12 years of age):  
CrCl (mL/min) = [(140 − age) × weight in kg] / [Scr × 72] (× 0.85 if female)  


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17.10. 
Blood Pressure Levels for Boys and Girls by Age and Height  
Figure 17.1: Blood Pressure Levels for Boys by Age and Height Percentile 
 


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Figure 17.2: Blood Pressure Levels for Girls by Age and Height Percentile 
 


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17.11. 
Growth Chart (2 to 20 years and Birth to 24 Months) 
Figure 17.3: Growth Chart (Boys 2 to 20 Years of Age) 
 


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Figure 17.4: Growth Chart (Girls 2 to 20 Years of Age) 
 


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Figure 17.5: Growth Chart (Boys Birth to 24 Months of Age) 
 


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Figure 17.6: Growth Chart (Girls Birth to 24 Months of Age)