Conditions: Deep Vein Thrombosis Venous Thromboembolism
Keywords: Pediatric Pharmacokinetics (PK) Pharmacodynamics (PDy) Anticoagulant Safety
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 66
Healthy volunteers: no

Brief summary:
This is the first evaluation of edoxaban in pediatric subjects. In this Phase 1 study, a single dose of edoxaban will be given to pediatric subjects who require anticoagulant therapy to see what the body does to the drug (pharmacokinetics) and what the drug does to the body (pharmacodynamics), and to compare if these effects are similar to those observed in adults.

Detailed description:
Phase 1, open-label, multiple-center study in pediatric patients from 0 to \< 18 years of age. Patients will receive a single dose of edoxaban to match either the 30 mg (low dose) or the 60 mg (high dose) exposure in adults. Exact doses will be selected during the study on the basis of PK modeling of emerging data. If unanticipated exposures are observed, the target doses may be modified to best match expected exposure response relationships observed in adults.

Enrollment in the study will start with the low dose, highest age group (adolescents) and will continue from low to high dose in each age group and from higher to lower age groups. Enrollment in the next dose/age cohort will begin after 50% of the subjects have completed the previous dose/age cohort.

Age cohorts and dose groups: (6 participants each in low and high dose groups, for a total of 12 participants per age cohort)

* 12 to \< 18 years of age
* 6 to \<12 years of age
* 2 to \<6 years of age
* 6 months to \<2 years of age
* 0 to \<6 months of age

Arms:
arm 1: 12 to \< 18 years of age: edoxaban low dose group arm 2: 12 to \< 18 years of age: edoxaban high dose group arm 3: 6 to \< 12 years of age: edoxaban low dose group arm 4: 6 to \< 12 years of age: edoxaban high dose group arm 5: 2 to \< 6 years of age: edoxaban low dose group arm 6: 2 to \< 6 years of age: edoxaban high dose group arm 7: 6 months to \<2 years of age: edoxaban low dose group arm 8: 6 months to \<2 years of age: edoxaban high dose group arm 9: 0 to 6 months of age: edoxaban low dose group arm 10: 0 to 6 months: edoxaban high dose group

Interventions: intervention 1: Edoxaban low dose intervention 2: Edoxaban high dose
Intervention descriptions: intervention 1: Edoxaban low dose intervention 2: Edoxaban high dose

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, 
NON-RANDOMIZED STUDY TO EVALUATE 
PHARMACOKINETICS AND PHARMACODYNAMICS 
OF EDOXABAN IN PEDIATRIC PATIENTS 
 
DU176b-A-U157 
 
IND NUMBERS 77,254 AND 63,266 
EUDRACT NUMBER 2015-005732-18 
VERSION 7.0, 16 SEP 2019 
PREVIOUS VERSION 6.0, 08 AUG 2018 
PREVIOUS VERSION 5.0, 14 JUL 2016 
PREVIOUS VERSION 4.0, 03 NOV 2015 
PREVIOUS VERSION 3.0, 21 JAN 2015 
PREVIOUS VERSION 2.0, 09 MAY 2014 
 
DAIICHI SANKYO, INC. 
211 MOUNT AIRY ROAD 
BASKING RIDGE, NJ 07920 USA 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc. (DSI), an 
unincorporated division of 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 DSI. 


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INVESTIGATOR AGREEMENT 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, NON-RANDOMIZED STUDY 
TO EVALUATE PHARMACOKINETICS AND PHARMACODYNAMICS 
OF EDOXABAN IN PEDIATRIC PATIENTS 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the DSI representative 
listed below. 
 
Print Name 
Signature 
Senior Director,  
Specialty Medicine   
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with 
the Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorization from the Sponsor.  It is, 
however, permissible to provide information to a patient in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Conference on 
Harmonization (ICH) guidelines on Good Clinical Practice (ICH E6), and applicable 
regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives, and relevant 
regulatory authorities, my patients’ study records in order to verify the data that I have 
entered into the Case Report Forms.  I am aware of my responsibilities as a Principal 
Investigator as provided by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study 
at any time for whatever reason; such a decision will be communicated to me in writing.  
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to the Sponsor. 
Print Name 
Signature 
Principal Investigator 
Title 
Date (DD MMM YYYY) 
PPD


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PROTOCOL SYNOPSIS 
EudraCT: 
2015-005732-18 
IND Numbers: 
IND 77,254 for Stroke, IND 63,266 for Deep Vein 
Thrombosis/Venous Thromboembolism 
Protocol Number: 
DU176b-A-U157 
Investigational Product: 
Edoxaban (free base of edoxaban tosylate) 
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: 
A Phase 1, Open-label, Single-dose, Non-randomized Study 
to Evaluate Pharmacokinetics and Pharmacodynamics of 
Edoxaban in Pediatric Patients 
Study Phase: 
Phase 1  
Indication Under 
Investigation: 
Not applicable. 
Study Objectives: 
Primary: 
 To characterize the PK of edoxaban in pediatric 
patients following single-dose oral administration 
Secondary: 
 To evaluate the PD effects of edoxaban in 
pediatric patients following single-dose oral 
administration 
 To evaluate the safety and tolerability of 
single-dose oral administration of edoxaban in 
pediatric patients 
 To assess metabolite exposure (D21-2393, 
D21-3231, D21-1402, and D21-2135) in pediatric 
patients 
 To evaluate the palatability (bitterness, sweetness, 
and overall taste or aroma) of the liquid oral 
suspension of edoxaban 


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Study Design: 
This is a Phase 1, open-label, multiple-center study in 
pediatric patients from 38 weeks gestation to < 18 years of 
age.  Patients from 5 age cohorts (12 evaluable patients per 
age cohort) will receive a single dose of edoxaban.  Each age 
cohort will be divided into a low- and high-dose group 
(6 patients per dose group).  Order of enrollment will be from 
the oldest age cohort to the youngest age cohort.  Within 
each age cohort, enrollment will first start in the lower dose 
group (to achieve exposures comparable to a 30 mg adult 
dose).  After evaluation of PK and safety data from at least 
half the patients in the lower dose group, enrollment may 
then start in the higher dose group (to achieve exposures 
comparable to a 60 mg adult dose).  If the observed 
exposures are higher than expected in the lower dose group 
and exceed the projected 60 mg adult exposure, then a lower 
dose may be investigated in the proposed “high-dose” group.  
Enrollment in the next younger age cohorts will begin when 
at least 50% of patients have completed the study in the older 
age cohort.  Enrollment in the younger age cohorts will start 
only after PK and safety data have been evaluated from 
at least 6 patients (3 low-dose and 3 high-dose) in the older 
age cohort.  Pharmacokinetic and safety data will be 
reviewed by a Data and Safety Monitoring Board (see 
Section 11.9) who will approve the start of the next younger 
age cohort.  However, enrollment initiation of Cohort 5 may 
be considered without PK and safety data from at least 50% 
of patients in the preceding older dose group. 
Age cohorts and dose groups: 
 12 to < 18 years of age on the day of dosing 
(12 evaluable total patients) 
 Cohort 1a: Low-dose group (6 patients) 
 Cohort 1b: High-dose group (6 patients) 
 6 to < 12 years of age on the day of dosing 
(12 evaluable total patients) 
 Cohort 2a: Low-dose group (6 patients) 
 Cohort 2b: High-dose group (6 patients) 


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 2 to < 6 years of age on the day of dosing 
(12 evaluable total patients) 
 Cohort 3a: Low-dose group (6 patients) 
 Cohort 3b: High-dose group (6 patients) 
 6 months to < 2 years of age on the day of dosing 
(12 evaluable total patients) 
 Cohort 4a: Low-dose group (6 patients) 
 Cohort 4b: High-dose group (6 patients) 
 38 weeks gestation to < 6 months of age on the 
day of dosing (12 evaluable total patients) 
 Cohort 5a: Low-dose group (6 patients) 
 Cohort 5b: High-dose group (6 patients) 
In Cohort 1, the oldest age group (12 to < 18 years), doses 
have been selected on the basis of modeling of adult data to 
target comparable exposures to 30 mg (low-dose) and 60 mg 
(high-dose).  In this cohort, fixed dosing will be used.  In 
Cohorts 2, 3, 4, and 5, the younger age groups (38 weeks 
gestation to < 12 years), appropriated doses will be selected 
to elicit target exposures comparable to those achieved from 
adult doses of 30 mg (low-dose) or 60 mg (high-dose).  
Patients in Cohort 1 will receive multiples of edoxaban 
tablets of 30 mg strength.  Patients in Cohorts 2, 3, 4, and 5 
will receive the edoxaban granule for oral suspension.  The 
dose that each dose group receives will be determined by 
Daiichi Sankyo based on emerging PK data and modeled 
doses needed to achieve target exposures. 
For patients in Cohort 1, 7 serial blood samples (2 mL per 
sample) will be collected for PK analysis based on a 
sampling windows approach: 0.25 to 1 hour, 1.5 to 3 hours, 
3.5 to 6 hours, 6.5 to 8 hours, 8.5 to 14 hours, 24 to 36 hours, 
and 48 to 54 hours postdose. Additionally, 6 serial PD blood 
samples (1.8 mL per sample) will be collected for estimation 
of biomarkers of coagulation (prothrombin time [PT], 
activated partial thromboplastin time [aPTT], and anti-
activated factor X [FXa]) at predose and immediately after 
simultaneously scheduled PK blood samples at 0.25 to 
1 hour, 1.5 to 3 hours, 3.5 to 6 hours, 6.5 to 8 hours, and 24 
to 36 hours postdose. 
For patients in Cohorts 2 and 3, 5 serial blood samples 
(patients 6 to < 12 years of age: 2 mL per sample and 


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patients < 6 years of age: 1 mL per sample) will be collected 
for PK analysis based on a sampling windows approach: 
0.25 to 1 hour, 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 
24 to 36 hours postdose. Additionally, 6 serial PD blood 
samples (patients 6 to < 12 years of age: 1.8 mL per sample 
and patients < 6 years of age: 1 mL per sample) will be 
collected for estimation of biomarkers of coagulation (PT, 
aPTT, and anti-FXa) at predose and immediately after 
simultaneously scheduled PK blood samples at 0.25 to 
1 hour, 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 
36 hours postdose. 
For patients in Cohort 4, 4 serial blood samples (600 µL per 
sample) will be collected for PK analysis based on a 
sampling windows approach: 0.5 to 2 hours, 3 to 8 hours, 
9 to 14 hours, and 24 to 36 hours postdose. Additionally, 
2 PD blood samples (1 mL per sample) will be collected for 
estimation of biomarkers of coagulation (PT, aPTT, and 
anti-FXa): once at the Screening Visit and once immediately 
after simultaneously scheduled PK blood sample at 0.5 to 
2 hours postdose. 
For patients in Cohort 5, blood samples (600 µL per sample) 
will be collected for PK analysis at a total of 3 of the 4 
possible timepoints postdose: 0.5 to 2 hours (mandatory), 
3 to 8 hours, 9 to 14 hours, and 24 to 36 hours. The 
timepoints will be assigned by the Sponsor once the subject 
is approved to be randomized. The Investigator will be 
informed of the PK timepoints to be collected for Cohort 5.  
Additionally, 2 PD blood samples (1 mL per sample) will be 
collected for estimation of biomarkers of coagulation (PT, 
aPTT, and anti-FXa): once at the Screening Visit and once 
immediately after simultaneously scheduled PK blood 
sample at 0.5 to 2 hours postdose. 
Although windows for sample collection are allowed, the 
exact time and date of each blood sample will be recorded in 
the patient’s Case Report Form. 


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Study Duration: 
The study will last approximately 4 weeks for each patient, 
which will include a screening period (within 21 days of 
dosing), a treatment period, and a follow-up visit conducted 
within 10 days after dosing.  However, a patient will be 
considered to have completed the study if they provide the 
last scheduled PK sample.  The treatment period will consist 
of predose procedures occurring on Day -1 or 1, dosing on 
Day 1, and postdose procedures occurring postdose on Days 
1, 2 (all cohorts) and Day 3 (all patients enrolled prior to 
Version 5.0 of the protocol may have had Day 3 PK samples 
obtained).  The treatment period days may occur as in-patient 
or out-patient based on the clinic’s ability/discretion.  The 
overnight stays are not mandatory.  Check-out procedures 
will be performed after the last PK/PD blood samples are 
collected (Day 2 or Day 3).   
The first patient is expected to be enrolled in June 2014. 
Study Sites and Location: 
Multiple sites in North America, Europe, and other regions  
Planned Sample Size: 
A total of 60 patients will be enrolled to obtain 12 evaluable 
patients in each age cohort (6 patients in each dose group). 
Patient Eligibility Criteria: 
Male and female pediatric patients who may require or are 
currently on anticoagulant therapy may be enrolled.   
These may include: 
 Patients who have a recently acquired or 
Investigator determined ongoing risk of 
thromboembolic events (e.g., patients with 
thrombophilia, congenital heart disease, presence 
of a central venous catheter and prior venous 
thromboembolic event [VTE]). 
 Patients who are completing their 
standard-of-care anticoagulant therapy. Edoxaban 
can be initiated 12 hours after cessation of 
enoxaparin, dabigatran, or apixaban therapy 
(A-U136, A-U151, and A-E152) and 24 hours 
after cessation of rivaroxaban therapy (A-U151). 
Note: that the dose of edoxaban should be at the 
time of the next scheduled standard-of-care 
anticoagulant administration: 
 At least 4 hours after last dose of 
unfractionated heparin. 


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 At least 12 hours after last dose of twice daily 
(bid) low molecular weight heparin (LMWH). 
 At least 24 hours after last dose of once daily 
(qd) LMWH and synthetic pentasaccharide 
(SP) Xa inhibitors. 
 For patients who were on a prior vitamin K 
antagonist (e.g., warfarin [C-U122] and any 
other anticoagulants) therapy, international 
normalization ratio (INR) value should be 
 2.5 prior to edoxaban dosing. If the patient’s 
INR is > 2.5, the patient’s INR should be 
monitored until it is  2.5. 
 Patients who are currently treated for VTE with at 
least 5 days of heparin may interrupt their 
standard-of-care anticoagulant therapy for 
edoxaban administration.  The dose of edoxaban 
should be: 
 At least 12 hours from last dose of bid 
LMWH, with a restart of LMWH 24 hours 
after edoxaban dose. 
 At least 24 hours from last dose of qd 
LMWH, with a restart of LMWH 24 hours 
after edoxaban dose. 
 Patients with cardiac conditions who may require 
anticoagulant therapy. 
 Patients with sickle cell disease who may require 
anticoagulant therapy. 
For any condition, anticoagulant treatment interruption or 
discontinuation should not take place if the patient is at 
increased risk and should be appropriate as per 
standard-of-care practices. 


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Dosage Form, Dose, and 
Route of Administration: 
Edoxaban tablets (30 mg) or edoxaban granules for oral 
suspension (60 mg reconstituted with 8 mL water to provide 
a 6 mg/mL suspension for oral administration).  In each age 
cohort, patients will receive appropriated single oral dose 
selected to target exposures comparable to adult doses of 
30 mg (low-dose) or 60 mg (high-dose).  If the observed 
exposure from the 30 mg dose in adolescents is higher than 
predicted and is comparable to the 60 mg adult dose 
exposures, then, the next cohort will receive a lower dose, 
instead of a higher dose.  To allow for this flexibility, 
patients in the 12 to < 18 years of age cohort will receive 
edoxaban tablets of 30 mg strength.  Patients younger than 
12 years of age will receive the edoxaban granule for oral 
suspension.  The dose amount given to each patient will be 
determined based on emerging data.  The dose given may be 
updated based on emerging data. 
The PK model will be refined based on emerging data, 
modeling of a target age and weight range will establish 
dosing paradigms.  The PK modeling will account for the 
range of weights. 
If a patient is unable or unwilling to ingest the assigned 
dosing form (tablet or suspension formulation), the patient 
will not be enrolled and will be replaced. 
Patients will be administered edoxaban in the morning with 
water.  
 Cohorts 1a/1b: 120 mL water;  
 Cohorts 2a/2b: 60 mL water;  
 Cohorts 3a/3b: 40 mL water;  
 Cohorts 4a/4b: 10 mL water;  
 Cohorts 5a/5b: 10 mL water.   
Patients will be asked to fast for at least 4 hours before 
dosing and for an additional 2 hours after dosing.  If this is 
not feasible because of the patient’s age or other needs, 
(unflavored) milk, or an equivalent substitute liquid (but not 
fruit juices), will be allowed until 1 hour before and starting 
at 1 hour postdose.  During this period, the total volume of 
liquids should not exceed 240 mL, excluding the volume of 
water utilized for dosing. 


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Study Endpoints: 
Pharmacokinetics: 
The PK endpoints will include modeled PK parameters such 
as apparent systemic clearance (CL/F), apparent volume of 
distribution (V/F), and area under the concentration-time 
curve (AUC) for edoxaban and metabolites, and 
metabolite/parent ratios for AUC. 
 
Pharmacodynamics: 
The PD endpoints will include observed, 
change-from-baseline, and percent-change-from-baseline PT, 
aPTT, and anti-FXa. 
Safety: 
Safety assessments will include: adverse events (AEs), 
physical examination findings, vital signs, standard 
hematology, clinical chemistry, and urinalysis laboratory 
tests.  Note: urinalysis will be performed with plastic bags 
with a sticky strip from neonates and infants with diapers. 
Other: 
Palatability of the liquid formulation will be assessed using 
visual analog scale (VAS) scores. 
Pharmacokinetics/ 
Pharmacodynamics/ 
Statistical Analyses: 
Plasma concentration-time data for edoxaban and metabolites 
(if data are available) will be listed by patient, age cohort 
and/or dose group, and measurement time interval, and will 
be plotted and summarized using descriptive statistics, as 
appropriate. Plasma concentration-time data for edoxaban 
and metabolites will be analyzed using model-based 
approaches such as nonlinear mixed effects modeling, where 
data from other studies may be pooled with pediatric data, 
and PK parameters will be calculated.  Estimated PK 
parameters will be assessed for age dependencies using 
graphical and/or modeling methods.  Estimated PK 
parameters will be listed and summarized by age cohort 
and/or dose group using descriptive statistics. 
An exploratory analysis of variance model will be applied to 
natural log-transformed CL/F, V/F, and AUC with age 
cohort, dose, and age cohort by dose interaction as fixed 
factors.  Appropriate adjustments on parameters, e.g., 
dose-normalization on AUC, or body weight-normalization 
on CL/F and V/F, might also be explored.  The least-squares 
mean differences between age cohorts with age cohort of 
12 to < 18 years as the reference and the corresponding 95% 


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confidence intervals (CIs) will be exponentiated to obtain 
point estimates of ratios of geometric means and the 
corresponding 95% CIs by dose level and/or overall (as 
appropriate). 
For PD biomarkers (PT, aPTT, and anti-FXa), observed, 
change-from-baseline, and percent-change-from-baseline 
data will be listed by patient, age cohort and/or dose group, 
and measurement time interval, and will be plotted and 
summarized using descriptive statistics, as appropriate. 
The PK/PD relationships will be examined graphically to 
assess age dependencies.  Additional PK/PD modeling may 
be conducted, if necessary, to understand age dependencies. 
The VAS scores for palatability will be listed and 
summarized by age cohort and/or dose group using 
descriptive statistics, if data permit. 
 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................12 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................19 
LIST OF ABBREVIATIONS ........................................................................................................20 
1. 
INTRODUCTION AND BACKGROUND INFORMATION .....................................22 
1.1. 
Data Summary ...............................................................................................................22 
1.1.1. 
Investigational Product..................................................................................................22 
1.1.1.1. 
Name .............................................................................................................................22 
1.1.1.2. 
Description ....................................................................................................................22 
1.1.1.3. 
Intended Use Under Investigation .................................................................................22 
1.1.1.4. 
Nonclinical Studies .......................................................................................................22 
1.1.1.5. 
Clinical Experience .......................................................................................................26 
1.2. 
Study Rationale .............................................................................................................28 
1.3. 
Dose Selection Rationale ..............................................................................................29 
1.4. 
Risks and Benefits for Study Patients ...........................................................................31 
1.5. 
Population, Route, Dosage, Dosage Regimen, and Treatment Period ..........................32 
1.6. 
Compliance Statement, Ethics, and Regulatory Compliance........................................33 
1.6.1. 
Patient Confidentiality ..................................................................................................33 
1.6.2. 
Informed Consent Procedure ........................................................................................33 
1.6.3. 
Regulatory Compliance .................................................................................................34 
2. 
STUDY OBJECTIVES AND HYPOTHESES .............................................................36 
2.1. 
Study Objectives ...........................................................................................................36 
2.1.1. 
Primary Objectives ........................................................................................................36 
2.1.2. 
Secondary Objectives ....................................................................................................36 
2.1.3. 
Exploratory Objectives..................................................................................................36 
2.2. 
Study Hypothesis ..........................................................................................................36 
3. 
STUDY DESIGN ..........................................................................................................37 
3.1. 
Overall Plan ...................................................................................................................37 
3.1.1. 
Study Type ....................................................................................................................37 


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3.1.2. 
Treatment Groups..........................................................................................................37 
3.1.3. 
Study Endpoints ............................................................................................................39 
3.1.4. 
Duration of the Study ....................................................................................................39 
3.1.5. 
Duration of Patient Participation ...................................................................................39 
3.1.6. 
Stopping Rules ..............................................................................................................39 
3.1.7. 
Steering Committee .......................................................................................................40 
3.2. 
Selection of Doses .........................................................................................................40 
3.2.1. 
Experimental Treatments ..............................................................................................40 
3.2.1.1. 
For the Study .................................................................................................................40 
3.2.1.2. 
For Individual Patients ..................................................................................................40 
3.2.2. 
Control Treatments........................................................................................................40 
4. 
STUDY POPULATION ...............................................................................................41 
4.1. 
Enrollment .....................................................................................................................41 
4.1.1. 
Inclusion Criteria ...........................................................................................................41 
4.1.2. 
Exclusion Criteria..........................................................................................................43 
4.2. 
Removal of Patients from Therapy ...............................................................................44 
4.2.1. 
Reasons for Withdrawal/Early Discontinuation............................................................44 
4.2.2. 
Withdrawal Procedures .................................................................................................45 
4.2.3. 
Patient Replacement ......................................................................................................45 
4.2.4. 
Patient Re-screening......................................................................................................45 
5. 
TREATMENTS ADMINISTERED .............................................................................47 
5.1. 
Investigational Products ................................................................................................47 
5.1.1. 
Method of Assigning Patients to Treatments and Blinding ..........................................47 
5.1.2. 
Method of Assessing Treatment Compliance ...............................................................47 
5.1.3. 
Labeling and Packaging ................................................................................................48 
5.1.4. 
Preparation ....................................................................................................................48 
5.1.5. 
Storage...........................................................................................................................48 
5.1.6. 
Drug Accountability ......................................................................................................48 
5.1.7. 
Retention Samples .........................................................................................................49 
5.2. 
Concomitant Medications .............................................................................................49 
5.3. 
Lifestyle Guidelines ......................................................................................................50 
6. 
STUDY PROCEDURES ..............................................................................................51 


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6.1. 
Screening .......................................................................................................................51 
6.2. 
Randomization ..............................................................................................................52 
6.3. 
Treatment Period ...........................................................................................................52 
6.3.1. 
Check-in and Treatment ................................................................................................52 
6.3.2. 
Check-in (Day -1/1 Predose) .........................................................................................52 
6.3.3. 
Treatment Period (Days 1 to 3) .....................................................................................53 
6.3.3.1. 
Day 1 .............................................................................................................................53 
6.3.3.2. 
Day 2 .............................................................................................................................55 
6.3.3.3. 
Day 3 .............................................................................................................................56 
6.4. 
Follow-up ......................................................................................................................56 
6.5. 
Protocol Deviations .......................................................................................................57 
7. 
EFFICACY ASSESSMENTS .......................................................................................58 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................59 
8.1. 
Pharmacokinetic Variable(s) .........................................................................................59 
8.1.1. 
Collection of Samples ...................................................................................................59 
8.1.2. 
Determination of Drug Concentrations .........................................................................60 
8.1.3. 
Rationale for Sample Collection Scheme .....................................................................60 
8.2. 
Pharmacodynamic Variable(s) ......................................................................................60 
8.2.1. 
Coagulation ...................................................................................................................60 
8.3. 
Biomarker and Exploratory Variable(s) ........................................................................61 
9. 
SAFETY ASSESSMENTS ...........................................................................................62 
9.1. 
Adverse Events..............................................................................................................62 
9.2. 
Safety Endpoints ...........................................................................................................62 
9.3. 
Definitions .....................................................................................................................62 
9.3.1. 
Adverse Event ...............................................................................................................62 
9.3.2. 
Serious Adverse Event ..................................................................................................63 
9.3.3. 
Adverse Event Severity .................................................................................................63 
9.3.4. 
Causality Assessment ....................................................................................................64 
9.3.5. 
Action Taken Regarding the Study Product .................................................................64 
9.3.6. 
Adverse Event Outcome ...............................................................................................64 
9.3.7. 
Other Action Taken for Event .......................................................................................65 
9.4. 
Serious Adverse Event Reporting – Procedure for Investigators..................................65 


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9.4.1. 
Initial Reports ................................................................................................................65 
9.4.2. 
Follow-up Reports .........................................................................................................65 
9.4.3. 
Notifying Regulatory Authorities, Investigators, and IRB/IEC ....................................66 
9.5. 
Exposure In Utero During Clinical Studies ..................................................................66 
9.6. 
Clinical Laboratory Evaluations ...................................................................................66 
9.7. 
Vital Signs .....................................................................................................................67 
9.8. 
Electrocardiograms .......................................................................................................67 
9.9. 
Physical Findings ..........................................................................................................67 
9.10. 
Other Safety Assessments .............................................................................................67 
10. 
OTHER ASSESSMENTS .............................................................................................68 
11. 
STATISTICAL METHODS .........................................................................................69 
11.1. 
Analysis Sets .................................................................................................................69 
11.1.1. 
Pharmacokinetic Analysis Set .......................................................................................69 
11.1.2. 
Pharmacodynamic Analysis Set ....................................................................................69 
11.1.3. 
Safety Analysis Set .......................................................................................................69 
11.2. 
General Statistical Considerations ................................................................................69 
11.3. 
Study Population Data ..................................................................................................69 
11.4. 
Efficacy Analyses..........................................................................................................69 
11.5. 
Pharmacokinetic/Pharmacodynamic Analyses .............................................................70 
11.5.1. 
Pharmacokinetic Analyses ............................................................................................70 
11.5.2. 
Pharmacodynamic Analyses .........................................................................................70 
11.6. 
Safety Analyses .............................................................................................................70 
11.6.1. 
Adverse Event Analyses ...............................................................................................70 
11.6.2. 
Clinical Laboratory Evaluation Analyses .....................................................................71 
11.6.3. 
Vital Sign Analyses .......................................................................................................71 
11.6.4. 
Physical Finding Analyses ............................................................................................71 
11.7. 
Other Analyses ..............................................................................................................71 
11.7.1. 
Palatability Analyses .....................................................................................................71 
11.8. 
Interim Analyses ...........................................................................................................71 
11.9. 
Data and Safety Monitoring Board ...............................................................................71 
11.10. 
Sample Size Determination ...........................................................................................71 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................72 


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12.1. 
Monitoring and Inspections ..........................................................................................72 
12.2. 
Data Collection..............................................................................................................72 
12.3. 
Data Management .........................................................................................................73 
12.4. 
Study Documentation and Storage ................................................................................73 
12.5. 
Record Keeping .............................................................................................................74 
13. 
FINANCING AND INSURANCE ...............................................................................75 
13.1. 
Finances.........................................................................................................................75 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................75 
14. 
PUBLICATION POLICY .............................................................................................76 
15. 
STUDY ADMINISTRATIVE INFORMATION .........................................................77 
15.1. 
Protocol Amendments ...................................................................................................77 
15.2. 
Address List ..................................................................................................................77 
15.2.1. 
Sponsor ..........................................................................................................................77 
15.2.1.1. Daiichi Sankyo, Inc. Medical Monitor ..........................................................................77 
15.2.1.2. Clinical Study Leader ....................................................................................................77 
15.2.1.3. Daiichi Sankyo, Inc. Clinical Study Manager ...............................................................77 
15.2.2. 
Clinical Research Organization.....................................................................................78 
15.2.2.1. Clinical Research Organization Medical Monitor ........................................................78 
15.2.2.2. Clinical Research Organization Project Manager .........................................................78 
15.2.3. 
Drug Safety ...................................................................................................................79 
15.2.3.1. Sponsor Serious Adverse Event Report Form General Contact ...................................79 
15.2.4. 
Data Management .........................................................................................................79 
15.2.5. 
Biological Pharmacokinetic Specimens ........................................................................79 
15.2.6. 
Biological Pharmacodynamic Specimens .....................................................................79 
15.2.7. 
Biological Specimens (Outside North America Only)..................................................79 
15.2.8. 
Clinical Safety Laboratory ............................................................................................79 
16. 
REFERENCES ..............................................................................................................80 
17. 
APPENDICES ..............................................................................................................81 
17.1. 
Additional Information on Investigational Products .....................................................81 
17.2. 
Instructions for Specimen Collection, Storage, and Shipment .....................................82 
17.2.1. 
Collection, Storage, Handling, and Shipping for Sample Analysis of Plasma 
Edoxaban (DU-176b) and Metabolites .........................................................................82 


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17.2.2. 
Collection, Storage, Handling, and Shipping of Blood Samples for 
Pharmacodynamic Analysis ..........................................................................................84 
17.3. 
Cytochrome P450 Clinically Significant Drug Interaction Table .................................86 
17.4. 
P-Glycoprotein Inhibitors and Inducers ........................................................................87 
17.4.1. 
P-gp Inhibitor Table ......................................................................................................87 
17.4.2. 
P-gp Inducers List (Prohibited Medication) ..................................................................87 
17.5. 
Modified Schwartz Equation (Pediatric Patients < 12 Years of Age) ..........................88 
17.6. 
VAS Patient Questionnaire ...........................................................................................89 
17.7. 
Schedule of Events ........................................................................................................91 
 
 


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LIST OF TABLES 
Table 1.1: Ex-vivo Inhibition of Coagulation Biomarkers by Edoxaban and 
Rivaroxaban (TMCP-Peds-001) .................................................................................26 
Table 17.1: Schedule of Events (All Cohorts) ...............................................................................91 
Table 17.2: Pharmacokinetic and Pharmacodynamic Blood Sampling Schedule for 
Cohort 1 ......................................................................................................................93 
Table 17.3: Pharmacokinetic and Pharmacodynamic Blood Sampling Schedule for 
Cohorts 2 and 3 ...........................................................................................................94 
Table 17.4: Pharmacokinetic and Pharmacodynamic Blood Sampling Schedule for 
Cohorts 4 and 5 ...........................................................................................................95 
 


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LIST OF FIGURES 
Figure 1.1: Simulated Plasma Concentration Time Profiles for Ages 12 to 18 Years 
(30 mg Dose) ..............................................................................................................30 
 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse event 
AF 
Atrial fibrillation  
ALT 
Alanine transaminase  
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
AUC 
Area under the concentration-time curve 
AUCtau 
Area under the concentration-time curve over the dosing interval 
bid 
Twice daily 
BMI 
Body mass index 
CES1 
Carboxylesterase 1 
CFR 
Code of Federal Regulations 
CHL/IU 
Chinese hamster lung cells 
CI 
Confidence interval 
CL/F 
Apparent systemic clearance 
CRF 
Case Report Form (electronic or paper) 
CRO 
Contract Research Organization 
CSPV 
Clinical Safety Pharmacovigilance 
CV% 
Coefficient of variation  
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic acid 
DSI 
Daiichi Sankyo, Inc. 
DSMB 
Data and Safety Monitoring Board 
EIU 
Exposure in utero 
FXa 
Activated factor X 
GCP 
Good Clinical Practice (refers to ICH and CFR) 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International normalization ratio  
IP 
Investigational product 
IRB 
Institutional Review Board  
LC-MS/MS 
Liquid chromatography with tandem mass spectroscopy  
LMWH 
Low molecular weight heparin 


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ABBREVIATION 
DEFINITION 
MedDRA 
Medical Dictionary for Regulatory Activities  
NOAEL 
No-observed-adverse-effect level 
OAT 
Organic anion transporters  
OCT 
Organic cation transporters 
PD 
Pharmacodynamic(s) 
P-gp 
P-glycoprotein  
PK 
Pharmacokinetic(s) 
PopPK 
Population based pharmacokinetic modeling 
PT 
Prothrombin time 
qd 
Once daily 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAVER 
Serious Adverse Event Report 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SP 
Synthetic pentasaccharide 
SUSAR 
Serious adverse event reactions 
TEAE 
Treatment-emergent adverse event 
TG 
Thrombin generation  
VAS 
Visual analog scale 
VTE 
Venous thromboembolic event 
V/F 
Apparent volume of distribution 
WBC 
White blood cell 
 


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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Data Summary 
A brief summary of relevant information from nonclinical and clinical studies included in the 
edoxaban (DU-176, free base of DU-176b) Investigator’s Brochure is included below.  Detailed 
information can be found in the Investigator’s Brochure.1 
1.1.1. 
Investigational Product 
1.1.1.1. 
Name 
Edoxaban tosylate (DU-176b): 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. 
1.1.1.2. 
Description 
Edoxaban is a potent and direct inhibitor of activated factor X (FXa) that prolongs clotting time 
of plasma.  Edoxaban has been approved in the United States and European Union for adults as a 
clinically useful anticoagulant.  In rat thrombosis models, this compound prevents thrombus 
formation and suppresses the hypercoagulable state. 
1.1.1.3. 
Intended Use Under Investigation 
Efficacy will not be studied in the protocol.  The goal of this study is to identify pediatric doses 
that provide comparable exposure to adult efficacious doses to guide dose selection for Phase 3 
studies in pediatrics. 
1.1.1.4. 
Nonclinical Studies 
Pharmacology 
Pharmacological studies demonstrate that edoxaban is a potent and selective inhibitor of 
activated FXa in vitro.  The in vitro anticoagulant effect of edoxaban is consistent with in vivo 
data.  Edoxaban does not impair platelet aggregation induced by collagen, U46619 (a 
thromboxane A2 agonist), or adenosine diphosphate in human platelet-rich plasma. 
The anticoagulant properties of edoxaban in vivo have been established in several rat thrombosis 
models: venous thrombus, disseminated intravascular coagulation, arterial-venous shunt, and 
venous stasis.  The minimal effective single oral doses in the in vivo models were 0.1 to 
2.5 mg/kg in rats yielding plasma edoxaban concentrations of about 5 to 170 ng/mL.  Plasma 
concentrations were generally proportional to the administered doses. 
There were no major safety pharmacology concerns with edoxaban. 
Absorption, Distribution, Metabolism, and Excretion 
In vitro protein binding of 14C-edoxaban was assessed in human plasma obtained from healthy 
volunteers (N = 3/concentration).  At concentrations of 0.2, 1, and 5 µg/mL, 54.3%, 54.4%, and 
56.6% of 14C-edoxaban, respectively, were bound to plasma protein. 


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In vitro distribution of 14C-edoxaban was assessed in human blood cells from plasma of healthy 
volunteers (N = 3/concentration).  At concentrations of 0.2, 1, and 5 µg/mL of 14C-edoxaban, 
45.7%, 45.9, and 47.4%, respectively, were distributed into the blood cells. 
In human liver microsomes, 6 edoxaban metabolites were identified:  D21-1402, D21-3231, 
D103-2684, D21-2393, D21-2135, and a hydroxylated metabolite at the N, N-dimethylcarbamoyl 
group of edoxaban.  Cytochrome P450 (CYP) 3A4 was the major enzyme involved in the 
formation of D21-1402, D103-2684, and M-3a.  D21-3231 and D21-2393 were formed 
independent of the reduced form of nicotinamide-adenine dinucleotide phosphate, indicating that 
they were not metabolized via CYP450 isozymes, but rather by a hydrolysis reaction.  D21-2135 
was considered a minor metabolite in this testing system. 
The enzymes involved in the hydrolysis of edoxaban to D21-2393 were characterized using 
pooled human liver microsomes, cytosolic, and recombinant human carboxylesterase 1 (CES1).  
The results demonstrated that edoxaban is metabolized to D21-2393 in the liver by human CES1. 
The P-glycoprotein (P-gp)-mediated transcellular transport of edoxaban and inhibitory effects of 
typical P-gp inhibitors on the vectorial transport of edoxaban were investigated using Caco-2 cell 
monolayers.  The results indicated that edoxaban is a substrate of the efflux transporter, P-gp.  
The uptake of 14C-edoxaban to S2 cells expressing transporter genes comprising human organic 
anion transporters (OAT) 1, OAT3, and human organic cation transporters (OCT) 2 was 
measured to elucidate the transport of edoxaban by human renal transporters.  These results 
suggest that edoxaban is not a substrate for OAT1, OAT3, and OCT2. 
The ontogeny of renal function, biliary secretion, P-gp, drug metabolizing enzymes CES 1 and 
CYP3A4, and gastric emptying and pH are likely to affect the pharmacokinetics (PK) of 
edoxaban for various pediatric age groups.  However, the ontogeny of all the enzymes and 
transporters is not very well characterized.  The kidneys are not fully mature at birth.  The 
glomerular filtration rate in neonates is 4 mL/1.73 m2, increasing rapidly to reach adult values by 
the end of first year.  The glomerular filtration rate continues to increase and overshoot adult 
levels until prepubescent age, resulting in higher renal clearance in children compared to adults.  
The tubular function also matures slowly and reaches adult levels by 1 year of age.2 
CYP3A4 has very low expression before birth, but increases rapidly, achieving 60% of adult 
levels between the ages of 6 and 12 months.  The CYP3A4 activity is slightly higher in infants 
than in adults.  The activity of CYP3A4 undergoes profound changes during all stages of 
development and is likely to affect drug metabolism in pediatrics.3,4  The ontogeny of P-gp is 
complicated, and there are conflicting literature reports, which suggest both developmental 
differences as well as differences in expression and function in various organs. 
Edoxaban absorption is likely to be affected by the gastric pH.  In neonates and at birth, the 
gastric pH values are close to neutral; within first 48 hours, pH decreases to 3 and by 3 months of 
age, the gastric pH is decreased further, closer to adult levels.  The gastric pH levels reach adult 
levels only by 2 years of age.  Gastrointestinal physiology also changes during development and 
may affect the absorption of drug.5 
The PK of edoxaban were investigated in rats and cynomolgus monkeys by measuring 
radioactivity following single oral doses of 3 and 1 mg/kg of 14C-edoxaban (as edoxaban) to rats 
and monkeys, respectively.  Wide-spread distribution of radioactivity following oral 


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administration of 14C-edoxaban occurred in the rat (albino) with the highest concentrations found 
in the gastrointestinal and bladder contents, followed by the kidney, preputial gland, liver, 
intestine, Harderian gland, pituitary gland, and nasal cavity.  In a tissue distribution study in 
pigmented rats, binding of edoxaban-related material occurred in ocular tissue and pigmented 
skin.  This suggests that edoxaban can bind to melanin.  In the monkey (pigmented), residual 
radioactivity at 336 hours was noted in the eyeball and skin, and trace amounts were present in 
the liver and kidney. 
Following oral administration of edoxaban, parent compound edoxaban was the predominant 
form found in monkey and rat plasma.  D21-3231 was the major metabolite found in rat plasma.  
Part of the D21-3231 found in the plasma may be from hydrolysis of edoxaban after sample 
collection, as edoxaban is unstable in rat plasma.  The assessment of metabolites in the urine and 
feces of rats and monkeys administered 14C-edoxaban by high-pressure liquid chromatography 
radio-chromatograms, and liquid chromatography with tandem mass spectroscopy (LC-MS/MS) 
assays showed that edoxaban was excreted largely unchanged.  Edoxaban and its metabolites do 
not undergo conjugation prior to elimination.  A plasma metabolite (D21-2393) found in humans 
was not detected radiometrically in rats and monkeys but trace amounts could be detected in 
excreta by LC-MS/MS.  Because D21-2393 is found in human plasma at higher concentrations 
than the trace amounts in animal excreta, D21-2393 is considered to be a human-specific 
metabolite. 
Toxicology 
The single oral dose toxicity studies in rats and monkeys indicate a relatively low acute toxicity 
potential for edoxaban.  Numerous chronic toxicology studies have been conducted in rats and 
cynomolgus monkeys with edoxaban dosing up to 52 weeks.  The data from these studies are 
described in detail in the Investigator’s Brochure.1 
In these studies, edoxaban treatment did not produce any remarkable or otherwise notable 
changes in body weight, electrocardiogram, ophthalmology, physical examination, and 
macroscopic and histopathologic examinations.  In the 52-week oral dosing study in cynomolgus 
monkeys, the no-observed-adverse-effect level (NOAEL) was estimated to be 5 mg/kg/day for 
males and females. 
Edoxaban did not show genotoxic potential in bacterial reverse mutagenic assays, but 
chromosomal (numerical) aberrations were noted in other in vitro studies after exposure to very 
high concentrations (at which the drug precipitates) of edoxaban.  Edoxaban did not show any 
genotoxic potential in bone marrow micronucleus tests in rats and cynomolgus monkeys, liver 
micronucleus test in rats, and unscheduled deoxyribonucleic acid (DNA) synthesis in rat liver.  
Since there was no damage to chromosomes or DNA in these in vivo studies, edoxaban is not 
considered to have genotoxic risk. 
In a rat fertility and early embryonic development study, there were no effects on male or female 
reproduction or early embryonic development at edoxaban doses up to 1,000 mg/kg/day.  In an 
embryo-fetal development study in rats given 30, 100, and 300 mg/kg/day, vaginal hemorrhage 
in dams and increased post-implantation loss occurred at 300 mg/kg/day.  The NOAEL was 
estimated to be 100 mg/kg/day. 


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In an embryo-fetal development study in rabbits given 60, 200, and 600 mg/kg/day, maternal 
toxicity (vaginal hemorrhage, abortion, and death) and fetotoxicity (post-implantation loss and 
decreased fetal weight) occurred at 200 and 600 mg/kg/day.  There were also increases in absent 
or small gall bladder of the fetuses at  200 mg/kg/day and an increase in 13th full ribs and 27th 
presacral vertebra at 600 mg/kg/day.  The NOAEL was estimated to be 60 mg/kg/day for dams, 
embryos, and fetuses. 
In the pre- and post-natal development study in rats given 3, 10, and 30 mg/kg/day, maternal 
toxicity (vaginal hemorrhage) and lower avoidance response rate in learning tests in the female 
offspring were observed on the first day of examination at 30 mg/kg/day, but not the second day 
of examination or in males.  The NOAEL was estimated to be 30 mg/kg/day for general toxicity 
in dams and 10 mg/kg/day for reproduction in dams and the development of next generation. 
Photosafety and eye function studies were performed because edoxaban distributed to ocular and 
skin tissues and bound to melanin in pigmented rats, as well as showed some absorption for light 
wavelengths greater than 290 nm.  Phototoxic potential was evaluated in an in vitro 
photochromosomal aberration test in Chinese hamster lung cells (CHL/IU) and in an in vitro 
phototoxicity test in BALB/3T3 cells.  Edoxaban did not show any phototoxic potential in either 
study.  In a 9-month eye function test in male and female cynomolgus monkeys given 
150 mg/kg/day, edoxaban did not affect any eye function parameter. 
To assess the toxicity of the human-specific metabolite D21-2393, a 14-day repeated oral dose 
toxicity study in rats and in vitro and in vivo genotoxicity studies were performed.  In the 14-day 
oral dose toxicity study, male and female rats were given D21-2393 at doses of 200, 600, and 
2,000 mg/kg/day and there was no treatment-related toxicity.  The NOAEL was estimated to be 
2,000 mg/kg/day for rats.  D21-2393 did not show any mutagenic potential in the bacterial 
reverse mutation test.  D21-2393 induced numerical chromosomal aberrations in CHL/IU cells at 
high concentrations (1,250 μg/mL or higher) but did not show any such aberrations in human 
lymphocytes.  Therefore, the observed polyploid induction in CHL/IU cells was not considered 
to be clinically relevant.  In addition, D21-2393 did not show any genotoxic potential in the bone 
marrow of rats given either a single dose or repeated doses up to 2,000 mg/kg/day in the 14-day 
repeated oral dose toxicity study.  Based on these results, D21-2393 is not considered to pose any 
genotoxic risk to humans.  In a juvenile toxicity study in rats, edoxaban tosylate hydrate did not 
show any effects on postnatal development and growth, organ development, skeletal 
development, or sexual maturation at doses up to 20 mg/kg/day. 
An ex vivo study (TMCP-Peds-001) evaluated the concentration-coagulation response 
relationship for edoxaban in neonatal (cord blood) and adult blood samples, using rivaroxaban as 
a positive control for establishing experimental conditions.  The range of edoxaban 
concentrations tested in this study was 12.5 to 500 ng/mL, which spans the therapeutic range of 
edoxaban.  Edoxaban induced dose-dependent inhibition of all coagulation parameters 
(prothrombin time [PT], activated partial thromboplastin time [aPTT], anti-FXa, Intrinsic factor 
X, and thrombin generation [TG]) (Table 1.1). 


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Table 1.1: 
Ex-vivo Inhibition of Coagulation Biomarkers by Edoxaban and 
Rivaroxaban (TMCP-Peds-001) 
PT 
aPTT 
Anti-
FXa 
Intrinsic 
FX 
TGA- 
Thrombin 
TGA- 
Lag 
TGA- 
Time 
to Peak 
TGA- 
VI 
TGA- 
ETP 
Edoxaban: 
Cord vs Adult 
NS 
102% 
NS 
97% 
N/A1 
NS 
99% 
NS 
109% 
NS 
111% 
NS 
105% 
NS 
115% 
NS 
94% 
Rivaroxaban: 
Cord vs Adult 
< 0.05 
114% 
NS 
112% 
NS 
87% 
NS 
114% 
< 0.05 
145% 
NS 
97% 
NS 
87% 
NS 
129% 
NS 
112% 
aPTT = activated partial thromboplastin time; ETP = endogenous thrombin potential; FXa = activated factor X; FX 
= factor X; N/A = not applicable; NS = non-statistically significant; PT = prothrombin time; TGA = thrombin 
generation assay; VI = velocity index. 
1. Due to 0 value at baseline, change from baseline could not be calculated. 
Ex vivo, there were no significant differences in inhibition of plasma biomarkers between adult 
and cord blood.  The pharmacodynamic (PD) effects of edoxaban in plasma from ex vivo-treated 
cord blood were not significantly different from that in plasma from ex vivo-treated adult blood 
for any parameter (see Table 1.1).  Differences fell within ± 10% for aPTT, Intrinsic FX, and 
2 out of the 5 TG parameters and ± 23% of the remaining endpoints (PT and 3 TG parameters).  
Thus, anticoagulant effects of edoxaban are found to be similar between adult plasma and cord 
blood.  These results concurred with previously published findings with rivaroxaban.6 Despite a 
difference in the baseline activity of various biomarkers, the potency of drug effects was similar 
between adults and cord blood. 
1.1.1.5. 
Clinical Experience 
Edoxaban is currently marketed in Japan (since 22 April 2011) for prevention of venous 
thromboembolic events (VTE) in patients with lower extremity orthopedic surgery (total hip 
replacement, total knee replacement, and hip fracture surgery).  It was further investigated 
worldwide in two Phase 3 clinical trials for reduction of stroke and systemic embolic events in 
patients with non-valvular atrial fibrillation and for treatment of acute VTE and prevention of 
recurrence in patients with symptomatic deep vein thrombosis and/or pulmonary embolism.  
Edoxaban has recently been approved in the United States, European Union, and Japan for stroke 
and systemic embolism prevention in atrial fibrillation (AF), and for treatment of VTE.  In the 
European Union, edoxaban is also approved for the prevention VTE.  It is also approved in Japan 
for VTE prophylaxis following orthopedic surgery. 
In the Phase 3 trial in AF patients, DU176b-C-U301 (ENGAGE AF-TIMI 48), a total of 
21,105 patients were randomized in the study.  Of these, 14,069 were randomized to edoxaban 
(7,034 to 30 mg once daily [qd] edoxaban; 7,035 to 60 mg qd edoxaban).  In the Phase 3 study in 
VTE patients, DU176b-D-U305 (Hokusai VTE), a total of 8,292 patients were randomized in the 
study.  A total of 4,143 patients were assigned to 60 mg qd edoxaban arm and 4,118 patients 
treated with edoxaban completed the study (8,250 patients completed the study).  
Approximately, 1,400 patients have received edoxaban in 45 Phase 1 studies. 
Approximately 1,300 human patients have been exposed to edoxaban in 45 completed Phase 1 
studies, as of 30 June 2012.  In healthy male patients, edoxaban was well tolerated with no 
evidence of major bleeding or clinically relevant liver function abnormality at repeated doses up 


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to 120 mg qd and 60 mg twice daily (bid) for 10 days and as single doses up to 180 mg.  
Consistent with the anticoagulant effect of edoxaban, minor, transient bleeding events were 
observed. 
In healthy adults, a 60 mg oral dose of edoxaban results in peak concentrations of 
309 ± 97 ng/mL.  Peak concentrations are achieved within 1 to 2 hours (Study A-U151 and 
Study A-U147).  The apparent terminal elimination half-life following oral administration is 
about 10 to 14 hours.  Following intravenous administration, the mean terminal elimination 
half-life was about 7 hours (Study A-U139).  The total clearance (arithmetic mean ± standard 
deviation [SD]) of edoxaban is estimated to be 21.8 ± 3.03 L/h with a steady-state volume of 
distribution of 107 ± 19.9 L (Study A-U139).  The absolute bioavailability of edoxaban is 
estimated to be about 62% (Study A-U139).  The PK profile of edoxaban is similar for single and 
multiple dosing.  Steady-state is achieved within 3 days of dosing, with minimal accumulation 
upon qd dosing (less than 2-fold).  The mean accumulation ratio at steady-state for Cmax is 1.07 
and for area under the concentration-time curve over the dosing interval (AUCtau) (over 
24 hours), is 1.14 (Study A-U151).  At steady-state, a 60 mg dose results in peak concentrations 
of 303 ± 88 ng/mL at median (range) time to maximum concentration values of 1.5 hour 
(0.5, 4.00 hour).  The steady-state exposure (AUCtau) is 1,990 ± 403 ng.h/mL, with trough 
concentrations of 15.5 ± 3.98 ng/mL (Study A-U151). 
Edoxaban is the active moiety and is the predominant circulating drug-related moiety.  In healthy 
adults, edoxaban undergoes both Phase 1 and 2 metabolism.  Phase 1 metabolism is 
predominantly mediated by CYP3A4 and CES1.  Metabolism by CES1 results in the formation 
of a human-specific metabolite D21-2393, which accounts for less than 10% of total edoxaban 
exposure in healthy adults.  Phase 2 metabolism is mediated by glucuronidation (Study PRT019).  
Seven metabolites have been identified.  Three of the metabolites (D21-2393, D21-2135, and 
D21-1402) are pharmacologically active with anticoagulant activity (BG11-H0026-R01).  
However, due to low abundance (< 10% for D21-2393 and < 5% for D21-2135 and D21-1402, 
each), the metabolites are not expected to contribute significantly to overall pharmacological 
activity of edoxaban in adults. 
Edoxaban is primarily eliminated unchanged in urine and through biliary secretion; with 
metabolism contributing to a lesser extent towards total clearance of edoxaban.  In healthy 
volunteers, edoxaban is the predominant excreted component in urine, accounting for 24% of the 
administered dose.  In feces, it accounts for 49% of administered dose (Study PRT019).  In 
healthy volunteers, renal and nonrenal clearances contribute equally (approximately 50% each) 
to the total clearance of edoxaban.  The human-specific metabolite, D21-2393, is not detected in 
urine and only about 2% is detected in feces (A-U139 and PRT019). 
In drug interaction studies with P-gp inhibitors (erythromycin, ketoconazole, cyclosporine, and 
verapamil), exposure of edoxaban increased, but the increase was generally less than 2-fold. 
Other drug interaction studies with inhibitors of P-gp and/or other CYPs (quinidine, amiodarone, 
and dronedarone) also resulted in less than 2-fold increase in edoxaban exposure. 
When edoxaban is dosed with a high-fat meal, there is no change in total exposure, but peak 
exposure increases by about 40%. 


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Concomitant administration of anti-platelet drugs (aspirin [100 and 325 mg qd × 5 days] and 
naproxen [500 mg bid × 2 days]) was assessed by investigating PK and bleeding times.  
Edoxaban exposure was either not affected or minimally affected by concomitant aspirin and 
naproxen.  In all 3 studies, bleeding times increased after administration of edoxaban, but to a 
lesser extent than those observed with either of the anti-platelet agents alone.  Administration of 
edoxaban in combination with the anti-platelet agents resulted in longer bleeding times than 
observed for any of the drugs alone.  The inter-study comparisons of edoxaban coadministered 
with either 100 or 325 mg aspirin indicated no significant difference in bleeding times by aspirin 
dose in these short-term studies.  Patients who received edoxaban and aspirin 325 mg had more 
bleeding adverse events (AEs) than those treated with edoxaban alone or aspirin alone.  
However, the data are limited and until there is further experience, the dose of aspirin 
coadministered with edoxaban should be limited to 100 mg in the absence of a compelling 
indication (e.g., acute myocardial infarction to reduce the risk of bleeding). 
Switching to edoxaban from other drugs has been studied in healthy adults.  Edoxaban can be 
initiated 12 hours after cessation of enoxaparin, dabigatran, or apixaban therapy (A-U136, 
A-U151, and A-E152) and 24 hours after cessation of warfarin or rivaroxaban therapy (C-U122 
and A-U151). 
The PD responses, specifically activated aPTT, PT, and anti-FXa activity, closely parallel the 
time course of plasma edoxaban concentrations.  On the basis of these biomarkers and others 
measuring thrombin generation, the onset of action for the anticoagulant effects of edoxaban is 
observed immediately after the first dose and maximum activity corresponds with maximum 
concentration (Cmax). 
Clinical (90 mg) and supra-therapeutic (180 mg) doses of edoxaban had no effect upon QTcI 
interval in the thorough QTc study, which was confirmed to have adequate sensitivity based on 
the QTcI effect of the positive control (moxifloxacin 400 mg).  Moreover, QTcF and QTcB 
methods yielded the same conclusion.  Systemic exposure (as defined by Cmax and area under the 
concentration-time curve [AUC] parameters) to edoxaban and its metabolite D21-2393 from the 
90 mg edoxaban dose was consistent with results from previous studies. 
Beriplex P/N, a 4-factor prothrombin complex concentrate has been evaluated as a potential 
reversal agent in a study in healthy volunteers.  In this study, bleeding duration (BD) 
prolongation after a punch biopsy was the primary end point.  Beriplex P/N dose-dependently 
reversed the effects of edoxaban on BD.  Complete reversal was observed following 50 IU/kg 
dose, partial reversal was observed following 25 IU/kg and no reversal was observed following 
10 IU/kg.  This treatment, however, has not been tested in patient populations with bleeding. 
Details of these and additional clinical studies are provided in the Investigator’s Brochure.1 
1.2. 
Study Rationale 
Edoxaban is an orally active, selective, reversible FXa inhibitor that is being developed as an 
anticoagulant for the treatment of venous thromboembolism including deep vein thrombosis, 
pulmonary embolism, and prevention of recurrent VTE.  The pivotal Phase 3 study (C-U305) 
was completed in 2012.  This is the first study in pediatric patients, ages 38 weeks gestation to 
< 18 years, in which, the PK/PD profile of edoxaban will be evaluated following a single-dose 
administration of oral edoxaban.  The goal of this study is to identify pediatric doses that provide 


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comparable exposure to adult efficacious doses to guide dose selection for Phase 3 studies in 
pediatrics.  Additional PK data will be obtained from Phase 3 studies in pediatrics. 
1.3. 
Dose Selection Rationale 
A 60 mg qd dosing regimen in adults was found to be safe and effective in the pivotal Phase 3 
trial in VTE patients.  Based on in vitro data, it appears that edoxaban has similar activity in 
adults and neonatal cord blood.  Hence, it is expected that doses that achieve similar exposures to 
the adult dose of 60 mg may be most effective in pediatric populations.  This study is designed to 
safely evaluate exposures of a low- and high-dose in each pediatric cohort, in order to guide 
dosing in a Phase 3 study in pediatrics.  The ex vivo study (TMCP-Peds-001) showed the 
anticoagulant effects of edoxaban are found to be similar between adult plasma and cord blood.  
Despite a difference in the baseline activity of various biomarkers, the potency of drug effects 
was similar between adults and cord blood.  The current study is targeting to have similar plasma 
exposure as in the adult Phase 3 VTE study with low (30 mg) and high exposure (60 mg).  For 
the younger age groups, it is planned to adjust the dose based on anticipated ontogeny 
differences and available data in the older pediatric age cohorts.  The starting dose for 
adolescents low-dose group was selected on the basis of population PK modeling (PopPK) and 
simulations (Figure 1.1).  The PopPK model was based on adult data (median age [range] 33 
[18 to 85] years; median body weight [range] 75.8 [42 to 165 kg]).  The basic structural model 
was a 2-compartment model with first-order absorption and lag time.  The simulation dataset 
consisted of 12 typical male patients from 12 to 18 years.  Body weight and height estimates 
were from the 2000 CDC (Centers for Disease Control and Prevention) Growth charts.7 
Creatinine clearance values were calculated using the Schwartz equation.8  A total of 
1,200 individuals were simulated.  A simulated 30 mg dose appears to provide similar or slightly 
lower mean exposure in the adolescent population. 


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Figure 1.1: 
Simulated Plasma Concentration Time Profiles for Ages 12 to 18 Years 
(30 mg Dose) 
 
 
Linear 
 
Semi-logarithmic 
 
 


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1.4. 
Risks and Benefits for Study Patients 
As described in United States regulations, this study is considered to fall into Title 21 Code of 
Federal Regulation (CFR) Part 50.53 as “Research involving greater than minimal risk and no 
prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge 
about the subject's disorder or condition.” 
The goal of this study is to identify pediatric doses that provide comparable exposure to adult 
efficacious doses in order to guide dose selection for Phase 3 studies in pediatrics.  
In pediatric patients the proportion of children developing recurrent VTE ranged from 3% in 
neonates to 8% in older children and as high as 21% in children reported with a first idiopathic 
VTE.  The results of meta-analyses indicate that 11% of children with nonidiopathic thrombosis 
overall develop a second VTE.11  Hence, this study offers a platform by which the identification 
of patients with non-idiopathic thrombosis or those with potential recurrence may be identified 
for future therapeutic care.   
In U157 study, the risk is considered as minimal for patients who already took anticoagulant 
therapy due to their health conditions.  U157 is a single dose study with a sequential enrolment 
(from older to younger) and with two tested doses (“low” dose to achieve exposures comparable 
to a 30 mg adult dose and “high” dose to achieve exposures comparable to a 60 mg adult dose).  
U157 patients are NOT healthy children; their health conditions already exposed them to 
procedures necessary to address their health problems related to thromboembolism.  In patients 
with no history of thromboembolic events, the risk is considered as a minor increase over 
minimal risk.  U157 risk was estimated based on experience with similar treatments and 
procedures in the pediatric population12 and from the well-known edoxaban effects in adults 
(Hokusai VTE Study).  U157 is a dose finding study with safety as a secondary objective.  The 
benefit to participate in U157 can be considered as direct for patients with health conditions 
exposing them to occurrence and/or recurrence of a thromboembolic event.  
U157 study also presents a reasonable opportunity to further the understanding, prevention, or 
alleviation of a serious problem affecting the health or welfare of children with thromboembolic 
disease.  The data derived from this study could potentially benefit pediatric patients when the 
study data is disclosed and becomes publically available or if it should lead to a possible update 
of the edoxaban label.  In addition, doses derived from this study will be implemented in Phase 3 
studies; in particular, patients with diagnosed VTE or cardiac diseases that may predispose them 
to venous or arterial thromboembolism. 
The research will be conducted in accordance with sound ethical principles, and adequate 
provisions are made for soliciting the assent of the children and the permission of their parents or 
legal guardians. 
The safety monitoring practices employed by this protocol (i.e., physical examinations, vital 
signs, AEs, and clinical laboratory assessments) in addition to periodic data review by a Data and 
Safety Monitoring Board (DSMB) are considered adequate to protect the patients’ safety. 
Please refer to the Investigator’s Brochure1 for the summary of clinical experience including side 
effects associated with edoxaban treatment. 


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1.5. 
Population, Route, Dosage, Dosage Regimen, and Treatment Period 
The study population will include patients 38 weeks gestation to < 18 years of age of both sexes, 
who may require, or are currently on anticoagulant therapy.   
These may include: 
 Patients who have a recently acquired or Investigator determined ongoing risk of 
thromboembolic events (e.g., patients with thrombophilia, congenital heart disease, 
presence of a central venous catheter and prior venous thromboembolic event [VTE]). 
 Patients who are completing their standard-of-care anticoagulant therapy. Note: that 
the dose of edoxaban should be at the time of the next scheduled standard-of-care 
anticoagulant administration: 
 At least 4 hours after last dose of unfractionated heparin. 
 At least 12 hours after last dose of bid low molecular weight heparin (LMWH). 
 At least 24 hours after last dose of qd LMWH and synthetic pentasaccharide (SP) 
Xa inhibitors. 
 For patients who were on a prior vitamin K antagonist (e.g., warfarin [C-U122] 
and any other anticoagulants) therapy, international normalization ratio (INR) 
value should be  2.5 prior to edoxaban dosing.  If the patient’s INR is > 2.5, the 
patient’s INR should be monitored until it is  2.5. 
 Patients who are currently treated for VTE with at least 5 days of heparin may 
interrupt their standard-of-care anticoagulant therapy for edoxaban administration.  
The dose of edoxaban should be: 
 At least 12 hours from last dose of bid LMWH, with a restart of LMWH 24 hours 
after edoxaban dose. 
 At least 24 hours from last dose of qd LMWH, with a restart of LMWH 24 hours 
after edoxaban dose. 
 Patients with cardiac conditions who may require anticoagulant therapy. 
 Patients with sickle cell disease who may require anticoagulant therapy.   
For any condition, anticoagulant treatment interruption or discontinuation should not take place 
if the patient is at increased risk and should be appropriate as per standard care of practices.  
The following dosage forms will be provided for this study: 
 Edoxaban 30 mg oral tablets for patients 12 and < 18 years of age. 
 Edoxaban granules for oral suspension (60 mg reconstituted with 8-mL water) to 
provide a 6 mg/mL suspension for oral administration for patients < 12 years of age. 
In each age cohort, appropriated doses will be selected to achieve exposures comparable to adult 
doses of 30 mg (low-dose) or 60 mg (high-dose).  If the observed exposure from the 30 mg dose 
in adolescents is higher than predicted and is comparable to the 60 mg adult dose exposures, 
then, the next cohort will receive a lower dose, instead of a higher dose.  To allow for this 


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flexibility, patients in the 12 to < 18 years of age cohort will receive edoxaban tablets of 30 mg 
strength.  Patients younger than 12 years of age will receive the edoxaban granule for oral 
suspension.  The dose amount given to each patient will be determined based on emerging data.  
The dose given may be updated based on emerging data. 
The PK model will be refined based on emerging data, modeling of a target age and weight range 
will establish dosing paradigms.  The PK modeling will account for the range of weights. 
1.6. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with this protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Conference on Harmonization (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
applicable regulatory requirement(s): 
 European Commission Directive (2001/20/EC Apr 2001) 
 European Commission Directive (2005/28/EC Apr 2005) 
 Food and Drug Administration GCP Regulations: CFR Title 21, parts 11, 50, 54, 56, 
and 312 
 The Health Insurance Portability and Accountability Act as appropriate and/or 
 Other applicable local regulations 
1.6.1. 
Patient Confidentiality 
The Investigator and the Sponsor will preserve the confidentiality of all patients taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the patient’s anonymity is maintained.  On the Case Report 
Form (CRF) or other documents submitted to Daiichi Sankyo, Inc. (DSI), patients should be 
identified by a unique patient identifier as designated by the Sponsor.  Documents that are not for 
submission to DSI (e.g., signed Informed Consent Forms [ICF]) should be kept in strict 
confidence by the Investigator. 
In compliance with federal regulations/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the company, of the regulatory agency(s), 
and the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) direct access 
to review the patient’s original medical records for verification of study-related procedures and 
data.  The Investigator is obligated to inform the patient that his/her study-related records will be 
reviewed by the above-named representatives without violating the confidentiality of the patient. 
1.6.2. 
Informed Consent Procedure 
Before a patient’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent and assent (generally, this age averages at 7 years of age), in writing, from the 
patient or legally acceptable representative after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any study drugs are administered.  A legally acceptable representative is 
an individual or other body authorized under applicable law to consent, on behalf of a 


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prospective patient, to the patient’s participation in the clinical study.  The written ICF should be 
prepared in the local language(s) of the potential patient population. 
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 IEC or IRB prior to being provided to potential patients. 
The patient’s written informed consent should be obtained prior to his/her participation in the 
study, and should be documented in the patient’s medical records, as required by 21 CFR Part 
312.62.  The ICF should be signed and personally dated by the patient or a legally acceptable 
representative, 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 patient or 
legal representative.  The date and time (if applicable) that informed consent was given should be 
recorded on the CRF. 
If the patient or legally acceptable representative cannot read, then according to ICH GCP 
Guideline, Section 4.8.9, an impartial witness should be present during the entire informed 
consent discussion.  This witness should sign the ICF after the patient or the legally acceptable 
representative has orally consented to the patient’s participation and, if possible, signed the ICF.  
By signing the ICF, the witness attests that the information in the ICF and any other written 
information was adequately explained to and apparently understood by the patient or the legally 
acceptable representative and that informed consent was freely given by the patient or the legally 
acceptable representative. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, etc.) 
and assent forms for pediatric patients (if applicable) are provided in the Sponsor ICF template 
for the Investigator to prepare the documents to be used at his or her site.  Updates to applicable 
forms will be communicated via letter from the Clinical Study Manager. 
According to 21 CRF 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 CRF 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 (i.e., separate assent forms for patients 7 to 
12 years and for patients 13 to 17 years) to ensure the assents maintain their “maturity levels and 
understandability.” 
1.6.3. 
Regulatory Compliance 
The study protocol, patient information and consent form, the Investigator’s Brochure, or written 
instructions to be given to the patient, available safety information, patient recruitment 
procedures (e.g., advertisements), information about payments and compensation available to the 


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patients, and documentation evidencing the Investigator’s qualifications should be submitted to 
the IEC 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 Statistical Analysis Plan. 
The Investigator must submit and, where necessary, obtain approval from the IEC or IRB for all 
subsequent protocol amendments and changes to the informed consent document or changes of 
the investigational site, facilities or personnel.  The Investigator should notify the IEC or IRB of 
deviations from the protocol or serious AEs (SAEs) occurring at the site and other AE reports 
received from DSI or Contract Research Organization (CRO), in accordance with local 
procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group will ensure all 
legal aspects are covered, and approval of 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 the appropriate notification of or approval by the relevant 
regulatory bodies. 


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2. 
STUDY OBJECTIVES AND HYPOTHESES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of this study is to characterize the PK of edoxaban in pediatric patients 
following single-dose oral administration. 
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate the PD effects of edoxaban in pediatric patients following single-dose 
oral administration 
 To evaluate the safety and tolerability of single-dose oral administration of edoxaban 
in pediatric patients 
 To assess metabolite exposure (D21-2393, D21-3231, D21-1402, and D21-2135) in 
pediatric patients 
 To evaluate the palatability (bitterness, sweetness, and overall taste or aroma) of the 
liquid oral suspension of edoxaban 
2.1.3. 
Exploratory Objectives 
No exploratory objectives are planned for this study. 
2.2. 
Study Hypothesis 
This is the first edoxaban pediatric study and is not intended to test a hypothesis, but rather to 
generate information that will allow dose selection for subsequent clinical efficacy/safety studies 
in pediatrics. 


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3. 
STUDY DESIGN 
3.1. 
Overall Plan 
3.1.1. 
Study Type 
This is a Phase 1, open-label, single-dose, non-randomized, multiple-center PK and PD study in 
pediatric patients.  The study will include 5 pediatric age cohorts with evaluation of 2 different 
doses within each age cohort (low- and high-dose). 
Age cohorts and dose groups: 
 12 to < 18 years of age on the day of dosing (12 evaluable total patients) 
 Cohort 1a: Low-dose group (6 patients) 
 Cohort 1b: High-dose group (6 patients) 
 6 to < 12 years of age on the day of dosing (12 evaluable total patients) 
 Cohort 2a: Low-dose group (6 patients) 
 Cohort 2b: High-dose group (6 patients) 
 2 to < 6 years of age on the day of dosing (12 evaluable total patients) 
 Cohort 3a: Low-dose group (6 patients) 
 Cohort 3b: High-dose group (6 patients) 
 6 months to < 2 years of age on the day of dosing (12 evaluable total patients) 
 Cohort 4a: Low-dose group (6 patients) 
 Cohort 4b: High-dose group (6 patients) 
 38 weeks gestation to < 6 months of age on the day of dosing (12 evaluable total 
patients) 
 Cohort 5a: Low-dose group (6 patients) 
 Cohort 5b: High-dose group (6 patients) 
A total of 60 patients will be enrolled such that 12 evaluable patients will be in each age cohort 
and 6 patients will be within each dose group.  Dropouts or patients with unusable data (for 
reasons other than AEs) may be replaced. 
3.1.2. 
Treatment Groups 
Patients will be dosed orally with a single dose of edoxaban on Day 1.  Patients in the 12 to 
< 18 years of age cohort will be dosed with multiples of edoxaban tablets of 30 mg strength.  
Patients younger than 12 years of age will receive the edoxaban granule for oral suspension.  The 
dosing amount and formulation type may change based on emerging data. 
If a patient is unable or unwilling to ingest the assigned dosing form (tablet or suspension 
formulation), the patient will not be enrolled and will be replaced. 


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Patients will be administered edoxaban in the morning with water. 
 Cohorts 1a/1b: 120 mL water;  
 Cohorts 2a/2b: 60 mL water;  
 Cohorts 3a/3b: 40 mL water;  
 Cohorts 4a/4b: 10 mL water;  
 Cohorts 5a/5b: 10 mL water.   
Patients will be asked to fast for at least 4 hours before dosing and for an additional 2 hours after 
dosing.  If this is not feasible because of the patient’s age or other needs, (unflavored) milk, or an 
equivalent substitute liquid (but not fruit juices), will be allowed until 1 hour before and starting 
at 1 hour postdose.  During this period, the total volume of liquids should not exceed 240 mL, 
excluding the volume of water utilized for dosing. 
Order of enrollment will be from the oldest age cohort to the youngest age cohort.  Within each 
age cohort, enrollment will first start in the lower dose group (to achieve exposures comparable 
to a 30 mg adult dose).  After evaluation of PK and safety data from at least half the patients in 
the lower dose group, enrollment may then start in the higher dose group (to achieve exposures 
comparable to a 60 mg adult dose).  If the observed exposures are higher than expected in the 
lower dose group and exceed the projected 60 mg adult exposure, then a lower dose may be 
investigated in the proposed “high-dose” group.  Enrollment in the next younger age cohorts will 
begin when at least 50% of patients have completed the study in the older age cohort.  
Enrollment in the younger age cohorts will start only after PK and safety data have been 
evaluated from at least 6 patients (3 low-dose and 3 high-dose) in the older age cohort.  
Pharmacokinetic and safety data will be reviewed by a DSMB (see Section 11.9) who will 
approve the start of the next younger age cohort.  However, enrollment initiation of Cohort 5 
may be considered without PK and safety data from at least 50% of patients in the preceding 
older dose group. 
In Cohort 1, the oldest age group (12 to < 18 years), doses have been selected on the basis of 
modeling of adult data to target comparable exposures to 30 mg (low-dose) and 60 mg 
(high-dose).  In this cohort, fixed dosing will be used.  In Cohorts 2, 3, 4, and 5, the younger age 
groups (38 weeks gestation to < 12 years), appropriated doses will be selected to elicit target 
exposures comparable to those achieved from adult doses of 30 mg (low-dose) or 60 mg 
(high-dose).  Patients in Cohort 1 will receive multiples of edoxaban tablets of 30 mg strength.  
Patients in Cohorts 2, 3, 4, and 5 will receive the edoxaban granule for oral suspension.  The 
dose that each dose group receives will be determined by Daiichi Sankyo based on emerging PK 
data and modeled doses needed to achieve target exposures. 
Study duration will be approximately 4 weeks for each patient, which will include a screening 
period (within 21 days of dosing), a treatment period, and a follow-up visit conducted within 
10 days after dosing.  However, a patient will be considered to have completed the study if they 
provide the last scheduled PK sample.  The treatment period will consist of predose procedures 
occurring on Day -1 or 1, dosing on Day 1, and postdose procedures occurring postdose on 
Days 1, 2 (all cohorts) and Day 3 (all patients enrolled prior to Version 5.0 of the protocol may 
have had Day 3 PK samples obtained).  The treatment period days may occur as in-patient or 


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out-patient based on the clinic’s ability/discretion.  The overnight stays are not mandatory.  
Check-out procedures will be performed after the last PK/PD blood samples are collected (Day 2 
or Day 3). 
An attempt will be made to have a balanced distribution of ages in each age cohort and dose 
group to provide maximum information regarding PK/PD and safety/tolerability.   
In each age cohort, appropriated doses will be selected to target exposures comparable to adult 
doses of 30 mg (low-dose) or 60 mg (high-dose).  This will be done on an ongoing basis, 
whereby emerging PK concentration-time data from completed patients will be analyzed on an 
ongoing basis and used to predict the doses required to obtain targeted exposures in upcoming 
age cohorts and dose groups.  Additionally, this ongoing PK analysis will be used to refine and 
optimize the PK blood sampling scheme (number of samples and timing) in upcoming age 
cohorts and dose groups. 
Refer to the Schedule of Events (Appendix 17.7) and study procedures (Section 6). 
3.1.3. 
Study Endpoints 
The PK endpoints will include modeled PK parameters such as apparent systemic clearance 
(CL/F), apparent volume of distribution (V/F), and area under the concentration-time curve 
(AUC) for edoxaban and metabolites, and metabolite/parent ratios for AUC. 
The PD endpoints will include observed, change-from-baseline, and percent-change-from-
baseline PT, aPTT, and anti-FXa. 
Safety assessments will include: AEs, physical examination findings, vital signs, standard 
hematology, clinical chemistry, and urinalysis laboratory tests.  Note: urinalysis will be 
performed with plastic bags with a sticky strip from neonates and infants with diapers. 
Palatability of the liquid formulation will be assessed using visual analog scale (VAS) scores. 
3.1.4. 
Duration of the Study 
The first patient is expected to be enrolled in June 2014. 
3.1.5. 
Duration of Patient Participation 
Approximately 4 weeks for each patient, which will include a screening period (within 21 days 
of dosing), a treatment period, and a follow-up visit conducted within 10 days after dosing.  
However, a patient will be considered to have completed the study if they provide the last 
scheduled PK sample. The treatment period will consist of predose procedures occurring on 
Day -1 or 1, dosing on Day 1, and postdose procedures occurring postdose on Days 1, 2 (all 
cohorts) and Day 3 (all patients enrolled prior to Version 5.0 of the protocol may have had Day 3 
PK samples obtained).  The treatment period days may occur as in-patient or out-patient based 
on the clinic’s ability/discretion.  The overnight stays are not mandatory.  Check-out procedures 
will be performed after the last PK/PD blood samples are collected. 
3.1.6. 
Stopping Rules 
Due to potential tolerability differences among age cohorts, stopping criteria will be applied 
independently to each age cohort.  The minimum intolerable dose will be defined as (1) the dose 


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at which a minimum of 60% of evaluable patients in an age cohort experiences more than 
1 occurrence of moderate or severe AEs, related to edoxaban or (2) the dose at which at least 
1 patient in an age cohort experiences an SAE judged to be medically serious and related to 
edoxaban as assessed by an independent DSMB.  The DSMB will be responsible for reviewing 
and assessing the available safety data as set forth in the DSMB Charter.  
3.1.7. 
Steering Committee 
A steering committee consisting of a panel of study Investigators or therapeutic area experts will 
be convened to provide clinical and scientific expertise to Daiichi-Sankyo on the design, 
execution, and analysis of this Phase 1 pediatric study. Responsibilities of the Steering 
Committee are set forth in the Steering Committee Charter. 
3.2. 
Selection of Doses 
3.2.1. 
Experimental Treatments 
Not applicable. 
3.2.1.1. 
For the Study 
Edoxaban will be evaluated in all patients in 1 treatment period.  Each patient will receive a 
single oral dose on Day 1.  In each age cohort, appropriated doses will be selected to achieve 
exposures comparable to adult doses of 30 mg (low-dose groups) and 60 mg (high-dose groups).  
The doses given to each age cohort and dose group will be adjusted based on emerging data. 
3.2.1.2. 
For Individual Patients 
The dose given to individual patients will be based on age cohort, body weight and targeted 
exposure as described in Section 3.2.1.1. 
3.2.2. 
Control Treatments 
Not applicable. 


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4. 
STUDY POPULATION 
4.1. 
Enrollment 
The Investigator will maintain a confidential screening log of all potential study candidates that 
includes limited information of the patients (initials, age [derived], and sex), date, and outcome 
of the screening process (e.g., enroll in the study, reason for ineligibility, and refused to 
participate). 
The Investigator will be expected to maintain an enrollment log of all patients enrolled in the 
study indicating their assigned study number. 
The Investigator will maintain a confidential patient identification code list.  This confidential 
list of names of all patients allocated to study numbers on enrolling in the study allows the 
Investigator to reveal the identity of any patient, when necessary. 
Patients will be considered enrolled upon obtaining informed consent (assent, when applicable) 
at randomization. 
Each patient or legally acceptable representative will sign an ICF and assent, if applicable, as 
required by country-specific regulatory authorities.  For additional information on informed 
consent, see Section 1.6.2. 
4.1.1. 
Inclusion Criteria 
Male and female pediatric patients who may require or are currently on anticoagulant therapy 
may be enrolled.   
These may include: 
 Patients who have a recently acquired or Investigator determined ongoing risk of 
thromboembolic events (e.g., patients with thrombophilia, congenital heart disease, 
presence of a central venous catheter and prior VTE). 
 Patients who are completing their standard-of-care anticoagulant therapy. Edoxaban 
can be initiated 12 hours after cessation of enoxaparin, dabigatran, or apixaban 
therapy (A-U136, A-U151, and A-E152) and 24 hours after cessation of rivaroxaban 
therapy (A-U151). Note: that the dose of edoxaban should be at the time of the next 
scheduled standard-of-care anticoagulant administration: 
 At least 4 hours after last dose of unfractionated heparin. 
 At least 12 hours after last dose of bid LMWH. 
 At least 24 hours after last dose of qd LMWH and SP Xa inhibitors. 
 For patients who were on a prior vitamin K antagonist (e.g., warfarin [C-U122] 
and any other anticoagulants) therapy, INR value should be  2.5 prior to 
edoxaban dosing.  If the patient’s INR is > 2.5, the patient’s INR should be 
monitored until it is  2.5. 


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 Patients who are currently treated for VTE with at least 5 days of heparin may 
interrupt their standard-of-care anticoagulant therapy for edoxaban administration.  
The dose of edoxaban should be: 
 At least 12 hours from last dose of bid LMWH, with a restart of LMWH 24 hours 
after edoxaban dose. 
 At least 24 hours from last dose of qd LMWH, with a restart of LMWH 24 hours 
after edoxaban dose. 
 Patients with cardiac conditions who may require anticoagulant therapy. 
 Patients with sickle cell disease who may require anticoagulant therapy. 
For any condition, anticoagulant treatment interruption or discontinuation should not take place 
if the patient is at increased risk and should be appropriate as per standard-of-care practices. 
Patients must satisfy all of the following criteria to be included in the study.  Any temporal 
changes in the following criteria that may prohibit patient consideration, but should normalize 
for future eligibility, should be reassessed for the patient’s future participation in the study: 
1. Patients/legal guardian(s) must be able to provide written informed assent (patient, when 
applicable) and ICFs (signed by parent/legal guardian) prior to participating in the study. 
2. Male or female patients 38 weeks gestation to  18 years of age on the day of dosing. 
3. Patients 2 to < 18 years of age must have a body mass index (BMI) between the 5th and 
95th percentile based on the 2000 CDC Growth Charts7 (the maximum number of patients 
in each dose group that have a BMI between the 85th and 95th percentile should not be 
more than 2 patients).  Patients < 2 years of age must have a body weight between the 5th 
and 90th percentile based on the 2000 CDC Growth Charts.7 
4. Female patients who have had menarche must test negative for pregnancy, as per local 
practice, at screening and check-in. 
5. Female patients who have had menarche and are sexually active must agree to use an 
effective contraception method, per local practice, for at least 30 days prior to edoxaban 
dose. 
6. Patients/legal guardian(s) must agree to food and drug restrictions during the study. 
 Patients must agree to abstain from and/or legal guardians must agree not to give 
the patient cola, tea, coffee, chocolate, and other caffeinated drinks and food from 
48 hours before dose administration to until after the last PK sample collection 
(see Section 5.3 for a complete list).  Mothers who are breastfeeding study 
patients should maintain this same dietary restriction for 24 hours prior to 
edoxaban dosing. 
 Patients must agree to abstain from and/or legal guardian(s) must agree not to 
give the patient St. John’s Wort and food/supplement and beverages containing 
grapefruit, grapefruit juice, and Seville oranges from 14 days before the first dose 
through to until after the last PK sample collection (see Section 5.3). 


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 Patients must agree to abstain from CYP3A4 inhibitors/inducers and P-gp 
inhibitors/inducers for 14 days prior to the edoxaban dose to until after the last PK 
sample collection (see Section 5.2). 
7. Patients must agree to abstain from the use of nonsteroidal anti-inflammatory drugs (such 
as ibuprofen) and antiplatelet (except for low-dose aspirin) from 14 days prior to 
edoxaban dose until after the last PK sample is collected.  Patients on low-dose aspirin 
treatment (1 to 5 mg/kg/day, maximum of 100 mg/day) are permitted to participate in the 
study per the Investigator’s judgment that this does not place the patients at risk.  
Low-dose aspirin on Day 1 should be withheld until 4 hours post edoxaban dose. 
8. Other than signs and symptoms characteristic to their disease state, patients are to be in 
good health as determined by the absence of clinically significant deviations from 
normal, with respect to medical and surgical history, physical examination, vital signs, 
and laboratory reports, as deemed by the Investigator prior to enrollment. 
4.1.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will be disqualified from entering the study. Any 
temporal changes in the following criteria that may prohibit patient consideration, but should 
normalize for future eligibility, should be reassessed for the patient’s future participation in the 
study: 
1. Patients with abnormal coagulation tests during screening, as defined by local laboratory 
reference ranges, which are not explained by anticoagulant therapy or temporary 
concomitant affections. 
2. Patients with stroke where anticoagulant therapy is contraindicated. 
3. Patients with stage 2 hypertension defined as blood pressure confirmed > 99th percentile 
+ 5 mmHg. 
4. Patients with renal function less than 50% of normal for age and size as determined by 
the National Kidney Disease Education Program version of the Schwartz formula (see 
Appendix 17.5).8 
5. Actively bleeding, has a high risk of bleeding, or has a history of major bleeding. 
6. Has a currently active gastrointestinal ulceration or a known history of peptic ulcer or 
gastrointestinal bleeding (including hematemesis, melena, or rectal bleeding including 
bleeding from hemorrhoids) within the previous 3 months. 
7. Has known diabetic retinopathy. 
8. Has thrombocytopenia at screening (< 20 × 109/L). 
9. Patients with history of major trauma, major or invasive procedures within the last month 
prior to screening. Otherwise, shorter time may be permitted depending on the surgery 
and based on the Investigator’s judgment of bleeding risk. 
10. Patients with known malabsorption disorders (e.g., cystic fibrosis or short bowel 
syndrome). Otherwise, shorter time may be permitted depending on the surgery and 
based on the Investigator’s judgment.  


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11. Hepatic disease which is associated with coagulopathy leading to a clinically relevant 
bleeding risk, alanine transaminase (ALT) > 5 times the upper limit of normal (ULN), or 
total bilirubin > 2 times the ULN with direct bilirubin > 20% of the total. 
12. Patient is currently enrolled in another investigational device or drug study or is receiving 
other investigational agents.  Patients must have completed the prior clinical study at least 
30 days prior to dosing. 
13. Patients of childbearing potential (post-menarche) who are sexually active and are not 
using approved contraception, per local practice; who are pregnant (as based on test 
results); or are breastfeeding. 
14. Females with history of abnormal menses, including history of menorrhagia (heavy 
menstrual bleeding), metrorrhagia, or polymenorrhea. 
15. Patient has known hypersensitivity to the active ingredient or any of the excipients of any 
compounds of the investigational product (IP) (see Appendix 17.1). 
16. Positive drug or alcohol screen (excluding cotinine) at screening for patients 12 years of 
age or older, neonates (0 to 28 days old), and for patients who are being breastfed. 
Exception to this is if patients are on prescription drug(s).  The window to potentially 
hold and/or resume the prescription drug will need to be determined by DSI based on the 
information of the prescription drug. 
17. Patients who have received a transfusion or any blood products within 30 days prior to 
the first dose. 
18. Patients with any condition that, as judged by the Investigator, would place the patient at 
increased risk of harm if he/she participated in the study or would interfere with the 
conduct of the study or the interpretation of the data. 
19. Patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome 
and are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 
2-glycoprotein I antibodies). 
4.2. 
Removal of Patients from Therapy 
4.2.1. 
Reasons for Withdrawal/Early Discontinuation 
Any patient who discontinues from the study treatment for any reason will have their study 
treatment discontinuation recorded.  A patient will be considered to have completed the study if 
they provide the last scheduled PK sample. 
Patients may be withdrawn from the study after signing informed consent for the following 
reasons: 
 AE. 
 Physician decision. 
 Withdrawal of consent by the following: 
 Child,  


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 Parent, or 
 Legal guardian. 
 Protocol violation. 
 Death. 
 Pregnancy. 
 Termination of all or part of the study by the Sponsor. 
 Other. 
If a patient withdraws 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 treatment and the 
reason for withdrawal. 
If the patient is withdrawn due to an AE, the Investigator will follow the patient until the AE has 
resolved or stabilized. 
All patients who are withdrawn from the study should complete protocol-specified withdrawal 
procedures (Section 4.2.2). 
4.2.2. 
Withdrawal Procedures 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason without penalty.  Every effort will be made to determine 
why any patient withdraws from the study prematurely.  This information should be recorded.  
All patients who withdraw from the study with an ongoing AE must be followed until the event 
is resolved or deemed stable.  If a patient withdraws prematurely after dosing, all data normally 
collected prior to study discharge should be collected at the time of premature discontinuation, or 
at the scheduled end-of-study visit.  A genuine effort must be made to determine the reason(s) 
why a patient fails to return for the necessary visits.  If the patient is unreachable by telephone, a 
registered letter, at the minimum, should be sent to the patient requesting him/her to contact the 
clinic. 
4.2.3. 
Patient Replacement 
Dropouts (for reasons other than AEs) may be replaced, if deemed necessary, upon written 
approval by the Sponsor.  A replacement patient will be within the same age cohort range and 
will receive the same dose and formulation of IP as the patient being replaced.  Any 
replacements will be made only after receiving the Sponsor’s written prior authorization. 
4.2.4. 
Patient Re-screening 
Re-screening of patients that fail to meet the Inclusion and Exclusion criteria is allowed if the 
reason for failure to meet the criteria has resolved and is no longer considered a risk to the 
patient (e.g., temporal laboratory deviations meeting exclusion criteria, treatment with 
contraindicated medications, non-chronic diagnoses). Re-screening of patients for this reason 
will be reviewed on a case-by-case basis and is dependent upon approval from the Medpace and 
Daiichi Sankyo Medical Monitors.  However, if a patient is screened but cannot dose for 


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personal/logistic reasons within 21 days of screening, they will need to be re-screened.  The 
exception is, patients that were previously on warfarin therapy and need to be within the 
acceptable range of INR values.  This will not be considered rescreening, and only INR values 
will be monitored at subsequent testing to ensure that prior to edoxaban dosing, the patient meets 
inclusion with INR  2.5. 


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5. 
TREATMENTS ADMINISTERED 
5.1. 
Investigational Products 
The Investigator must ensure that the IP will be used only in accordance with the protocol. 
According to ICH GCP 1.33, an IP is a pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical study.  This includes products with marketing 
authorizations when used or assembled (formulated or packaged) in a way different from the 
approved form or when used for an unapproved indication, or when used to gain further 
information about an approved use. 
The IP for this study is edoxaban (DU-176b) in any of the following formulations: 
 Edoxaban 30 mg oral tablets. 
 Edoxaban granules for oral suspension (60 mg reconstituted with water to provide a 
6 mg/mL suspension for oral administration). 
Edoxaban doses will be appropriated to achieve exposures comparable to adult doses of 30 mg 
(low-dose) and 60 mg (high-dose).  Patients in the 12 to < 18 years of age cohort will receive 
multiples of edoxaban tablets of 30 mg strength.  Patients < 12 years will receive the liquid oral 
suspension formulation. 
5.1.1. 
Method of Assigning Patients to Treatments and Blinding 
This will be an open-label study.  This study is not randomized.  Patients will receive edoxaban 
on 1 occasion.  Enrollment will first start in the lower dose group of the oldest age cohort (to 
achieve exposures comparable to a 30 mg adult dose).  After evaluation of PK and safety data 
from at least half the patients in the lower dose group, enrollment will start in the higher dose 
group (to achieve exposures comparable to a 60 mg adult dose).  If the observed exposures are 
higher than expected in the lower dose group and exceed the projected 60 mg adult exposure 
then a lower dose may be investigated in the proposed “high-dose” group.  Enrollment in the 
next younger age cohorts will begin when PK and safety data from at least 50% (N = 6) of 
patients in the preceding older dose group have been reviewed.  Pharmacokinetic and safety data 
will be reviewed by a DSMB (see Section 11.9) who will approve the start of the next younger 
age cohort.  However, enrollment initiation of Cohort 5 may be considered without PK and 
safety data from at least 50% of patients in the preceding older dose group.  An attempt will be 
made to enroll patients spanning the entire age range for each age cohort. 
5.1.2. 
Method of Assessing Treatment Compliance 
The following measures will be employed to ensure treatment compliance.  The single dose of IP 
should be administered under the supervision of clinical study personnel.  For patients receiving 
the tablet formulation, a mouth and hand check of all patients should be carried out to ensure that 
all tablets have been swallowed, if applicable.  For patients receiving the liquid oral suspension 
the clinic personnel will check and record whether any of the liquid is spit out or lost to drooling. 


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5.1.3. 
Labeling and Packaging 
Investigational products will be packaged and labeled in an open-label format.  Clinical study 
labels will include study number, contents, quantity, lot number, directions, storage conditions, 
CAUTION statement as required by country/region, and Sponsor information.  In addition, oral 
syringes for dosing of reconstituted suspension will be provided by the Sponsor. 
Edoxaban 30 mg tablets, expressed as the anhydrous free base, will be supplied by the Sponsor 
in blister cards containing 30 tablets, in an open-label format.  The 60 mg edoxaban granules for 
reconstitution, will be packaged in amber glass bottles (wide neck) with white polypropylene 
caps, and supplied by the Sponsor.   
5.1.4. 
Preparation 
The IP will be provided as tablets and as a granule for oral suspension formulation. 
No special preparation will be required for the tablet formulation.   
For edoxaban (DU-176b) granule for oral suspension 60 mg, investigational product will be 
supplied in amber glass bottles (wide neck) with white polypropylene caps.  The medication 
requires reconstitution with water and must be freshly prepared just prior to administration 
(within 30 minutes).  The total amount of diluent (non-carbonated water) to be added is 8 mL, 
and added in 1 part.  After reconstitution, the resultant drug concentration will be 6 mg/mL.  The 
maximum amount of medication will be 10 mL.  Aliquots appropriate to provide the required 
dose will be withdrawn from this 10 mL suspension.  Before aliquoting, the bottle must be 
shaken.  The edoxaban suspension is a single-use preparation for immediate use and is not 
intended to be stored. 
5.1.5. 
Storage 
Investigational products (edoxaban tablets and granules for reconstitution) must be stored at 20° 
to 25°C (68° to 77°F), with excursions permitted to 15° to 30°C (59° to 86°F).  Drug supplies 
must be stored in a secure, limited access storage area under the recommended storage 
conditions.  If storage conditions go outside of the specified range, DSI should be contacted.  
The excursions will be discussed with the Sponsor to determine what action is necessary. 
5.1.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition and temperature recording of the drug, check for appropriate local language in the 
label, drug expiration date, and sign the Receipt of Shipment Form provided.  The Receipt of 
Shipment Form should be faxed as instructed on the form.  The original will be retained at the 
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 resolution is obtained 
from the Sponsor. 


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A Drug Accountability Record will be used for the IP, and can be provided by the 
Sponsor/Sponsor representative, or the site can use a Sponsor Approved Form.  The record must 
be kept current and should contain the dates and quantities of drug received, patients for whom 
the IP was dispensed (identification number and/or initials or supply number as applicable), the 
date and quantity of IP dispensed and remaining, if from individual patient drug units, as well as 
the initials of the dispenser. 
At the end of the study, or as directed, all IP, including unused, partially used, or empty 
containers, will be destroyed at the clinic.  The IP will only be returned to a designee as 
instructed by the Sponsor if the clinic is unable to perform the IP destruction. Dosage form 
(ie, tablet, granule bottle) site level accountability documentation is required as part of the 
disposition records of the investigational product.  The dosage form site level accountability 
documentation should be appended to the Certificate of Destruction. 
Investigational product will be returned only after the study monitor has completed a final 
inventory to verify the quantity to be returned.  The return/destruction of IP must be documented.  
Dosage form (ie, tablet, granule bottle) site level accountability documentation must 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. 
At the end of the study, a final IP reconciliation statement must be completed by the Investigator 
or designee and provided to the Sponsor.  Unused drug supplies may be destroyed by the 
Investigator when approved in writing by the Sponsor and the Sponsor has received copies of the 
site’s drug handling and disposition standard operating procedures (SOPs). 
All IP 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 site. 
5.1.7. 
Retention Samples 
Retention samples will be collected and stored in countries where required by regulations. 
5.2. 
Concomitant Medications 
For the below specified number of days through study completion or upon early withdrawal, the 
following medications are not allowed: 
 Use of P-gp inhibitors or inducers (see Appendix 17.4) within 14 days prior to the 
edoxaban dose until after the last PK sample is collected. 
 Use of any CYP3A4 inhibitors/inducers (see Appendix 17.3) for 14 days prior to 
edoxaban dose to until after the last PK sample is collected. 


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 Use of nonsteroidal anti-inflammatory drugs (such as ibuprofen), and antiplatelet 
(except low-dose aspirin [1 to 5 mg/kg/day, maximum of 100 mg/day]) from 14 days 
prior to edoxaban dose to until after the last PK sample is collected. Patients on 
low-dose aspirin treatment (1 to 5 mg/kg/day, maximum of 100 mg/day) are 
permitted to participate in the study per the Investigator’s judgment that this does not 
place the patients at an unacceptable bleeding risk. Low-dose aspirin on Day 1 should 
be withheld until 4 hours post edoxaban dose. 
During the study, concomitant mediations required for care of treatment-emergent AEs (TEAEs) 
will be permitted; although, where possible, the Investigator should speak with the DSI Medical 
Monitor and Study Director before prescribing such medication.  For treatment of pain or for 
analgesic use, if needed, acetaminophen is recommended. 
Any medication (other than study drug) taken by patients during the course of the study will be 
recorded and coded using the World Health Organization drug dictionary.  If drug therapy other 
than that specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
5.3. 
Lifestyle Guidelines 
At screening, patients/legal guardians will be informed that if accepted for the study, no 
St. John’s Wort or foods/supplements or beverages containing grapefruit, grapefruit juice, or 
Seville oranges are allowed for 14 days prior to dosing to until after the last PK specimen 
collection.  Patients must agree to abstain from and/or legal guardians must agree not to give the 
patient cola, tea, coffee, chocolate, and other caffeinated drinks and food from 48 hours before 
dose administration through the end of the last PK specimen collection.  Mothers who are 
breastfeeding study patients should maintain this same dietary restriction for 24 hours prior to 
edoxaban dosing. 


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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Appendix 17.7.  To minimize pain and 
distress for pediatric patients, the following measures are allowed: 
 Use of topical anesthetics  
 Use of indwelling cannula 
However, heparin should not be used for flushing the cannula. 
6.1. 
Screening  
Screening will take place within a 3-week window (Days -21 to -2) before dosing.  Informed 
consent will be obtained from the patient/guardian prior to performing any of the screening 
assessments.  For information regarding re-screening, see Section 4.2.4. 
The following activities and/or assessments will be performed at/during screening: 
 Informed consent (for parent/legal guardian/patient) and depending on the age of the 
patient, an assent form may also be signed by the patient.  
 Inclusion/exclusion criteria. 
 Record demographic information (date of birth/age, sex, ethnicity, and race). 
 Medical and surgical history, including medication history. 
 AE monitoring. 
 Concomitant medication monitoring. 
 Physical examination, including height, weight, and BMI (derived). 
 Pregnancy test based on local practice (for post-menarchal females). 
 Patients of childbearing potential (post-menarche) who are sexually active must agree 
to use an effective contraception method, per local practice, for the duration of the 
study. 
 Blood samples for: 
 Clinical laboratory tests (hematology and serum chemistry) if not performed 
within 2 weeks prior to screening (refer to Section 9.6). 
 Coagulation (PT, INR, and aPTT). 
 Serology (human immunodeficiency virus [HIV] and hepatitis B and C testing) if 
not performed within 2 weeks prior to screening. 
 PD blood samples for Cohorts 4 and 5. 


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 Urine sample for: 
 Urine drug screen for the presence of the following controlled substances: opiates, 
benzodiazepines, amphetamines, cannabinoids, cocaine, barbiturates, 
phencyclidine, cotinine levels (non-exclusionary), and alcohol will be performed 
on patients 12 years of age and older, for newborns, and for patients who are 
being breastfed. 
 Urine sample for dipstick analysis. Microscopic analysis may be required if 
dipstick is positive for blood, RBC, or WBC. 
 Vital signs including blood pressure, pulse rate, and body temperature after resting at 
least 5 minutes in a sitting or supine position.  (Note: the appropriate cuff size based 
on arm circumference will be used). 
6.2. 
Randomization 
This is not a randomized study.  In each age group, patients will be assigned to a particular 
treatment in a manner that allows for an even distribution of ages across doses (this decision will 
be made in consultation with clinical study lead). 
6.3. 
Treatment Period 
6.3.1. 
Check-in and Treatment 
The following procedures apply to check-in and treatment, as appropriate.  
Patients will be asked to fast for at least 4 hours before dosing and for an additional 2 hours after 
dosing.  If this is not feasible because of the patient’s age or other needs, (unflavored) milk, or an 
equivalent substitute liquid (but not fruit juices), will be allowed until 1 hour before dosing and 
starting at 1 hour postdose.  During this period, the total volume of liquids should not exceed 
240 mL, excluding the volume of water utilized for dosing. 
6.3.2. 
Check-in (Day -1/1 Predose) 
Check-in is scheduled for Day -1; however, check-in may also occur on Day 1 prior to dosing at 
the clinic’s discretion.  Patients may be confined from time of check-in until after the last 
assessment is made on Day 2 (or Day 3 for patients enrolled prior to Version 5.0 of the protocol); 
however, overnight stays are not required. 
The following activities and/or assessments will be performed at/during check-in: 
 Reassessment of eligibility. 
 Medical and surgical history, including medication history. 
 Physical examination, including height, weight, and BMI (derived). 
 Pregnancy test based on local practice (for post-menarchal females). 


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 Urine sample for: 
 Urine drug screen for the presence of the following controlled substances: opiates, 
benzodiazepines, amphetamines, cannabinoids, cocaine, barbiturates, 
phencyclidine, cotinine levels (non-exclusionary), and alcohol will be performed 
on patients 12 years of age and older, for newborns, and for patients who are 
being breastfed. 
 Urine sample for dipstick analysis. Microscopic analysis may be required if 
dipstick is positive for blood, RBC, or WBC. 
 Vital signs including blood pressure, pulse rate, and body temperature after resting at 
least 5 minutes in a sitting or supine position.  (Note: the appropriate cuff size based 
on arm circumference will be used.) 
 AE monitoring. 
 Concomitant medication monitoring. 
6.3.3. 
Treatment Period (Days 1 to 3) 
6.3.3.1. 
Day 1 
On Day 1, the following procedures will be performed after the patient has fasted for at least 
4 hours (patients will continue to fast until 2 hours postdose).  Patients who have not fasted must 
return on a subsequent day for Day 1 treatment.  Any procedure occurring after hour 8 on Day 1 
may be performed using a home healthcare service, depending on the availability of the service 
in the patient’s country:  
 All Cohorts: 
o Edoxaban administration. 
o Assessment of palatability for patients or guardians of patients receiving the 
edoxaban granule for oral suspension formulation (including bitterness, 
sweetness, overall taste, and aroma) using 100 mm VAS. 
o AE monitoring. 
o Concomitant medication monitoring.  
 Cohort 1: 
o Vital signs (including, blood pressure, pulse rate, and body temperature) will be 
taken before dose administration and within the following windows: 0.25 to 
1 hour, 1.5 to 3 hours, and 8.5 to 14 hours postdose. All vital sign assessments 
will be performed before the scheduled blood sampling for edoxaban and after at 
least a 5-minute rest in a sitting or supine position. The position is which the vital 
signs are taken (i.e., sitting or supine) will be recorded in the CRF. 


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o Serial PK blood samples will be collected after edoxaban administration using a 
window approach at 0.25 to 1 hour, 1.5 to 3 hours, 3.5 to 6 hours, 6.5 to 8 hours, 
and 8.5 to 14 hours postdose. 
o Serial PD blood samples for estimation of biomarkers of coagulation (aPTT, PT, 
and anti-FXa) will be collected at predose and immediately after simultaneously 
scheduled PK sample collections at 0.25 to 1 hour, 1.5 to 3 hours, 3.5 to 6 hours, 
and 6.5 to 8 hours. 
 Cohorts 2 and 3: 
o Vital signs (including, blood pressure, pulse rate, and body temperature) will be 
taken before dose administration and within the following windows: 0.25 to 
1 hour, 1.5 to 3 hours, and 9 to 14 hours postdose. All vital sign assessments will 
be performed before the scheduled blood sampling for edoxaban and after at least 
a 5-minute rest in a sitting or supine position. The position is which the vital signs 
are taken (i.e., sitting or supine) will be recorded in the CRF. 
o Serial PK blood samples will be collected after edoxaban administration using a 
window approach at 0.25 to 1 hour, 1.5 to 3 hours, 4 to 8 hours, and 9 to 14 hours 
postdose. 
o Serial PD blood samples for estimation of biomarkers of coagulation (aPTT, PT, 
and anti-FXa) will be collected at predose and immediately after simultaneously 
scheduled PK sample collections at 0.25 to 1 hour, 1.5 to 3 hours, 4 to 8 hours, 
and 9 to 14 hours postdose. 
 Cohort 4: 
o Vital signs (including, blood pressure, pulse rate, and body temperature) will be 
taken before dose administration and within the following windows: 0.5 to 
2 hours, 3 to 8 hours, and 9 to 14 hours postdose. All vital sign assessments will 
be performed before the scheduled blood sampling for edoxaban and after at least 
a 5-minute rest in a sitting or supine position. The position is which the vital signs 
are taken (i.e., sitting or supine) will be recorded in the CRF. 
o Serial PK blood samples will be collected after edoxaban administration using a 
window approach at 0.5 to 2 hours, 3 to 8 hours, and 9 to 14 hours postdose.  
o PD blood samples for estimation of biomarkers of coagulation (aPTT, PT, and 
anti-FXa) will be collected immediately after simultaneously scheduled PK 
sample collection at 0.5 to 2 hours postdose. 


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 Cohort 5: 
o Vital signs (including, blood pressure, pulse rate, and body temperature) will be 
taken before dose administration and within the following windows: 0.5 to 
2 hours, 3 to 8 hours, and 9 to 14 hours postdose. All vital sign assessments will 
be performed before the scheduled blood sampling for edoxaban and after at least 
a 5-minute rest in a sitting or supine position. The position is which the vital signs 
are taken (i.e., sitting or supine) will be recorded in the CRF. Note: Patients will 
receive either 2 or 3 of these vital signs recordings depending on which PK blood 
sample timepoints they are assigned. 
o PK blood samples will be collected after edoxaban administration at a total of 3 of 
the 4 possible timepoints postdose: 0.5 to 2 hours (mandatory), 3 to 8 hours, 9 to 
14 hours, and 24 to 36 hours (on Day 2). The timepoints will be assigned by the 
Sponsor once the subject is approved to be randomized.  
o PD blood samples for estimation of biomarkers of coagulation (aPTT, PT, and 
anti-FXa) will be collected immediately after simultaneously scheduled PK 
sample collection at 0.5 to 2 hours postdose. 
Exact dates and times of dosing and sample collection will be recorded in the patients’ CRFs and 
used for analyses.  At time points when PK, and PD blood samplings occur at the same time, the 
PK blood samples will be collected first and then PD blood samples will be collected. An 
overnight stay on Day 1 is not mandatory. 
6.3.3.2. 
Day 2 
On Day 2, the following procedures will be performed: 
 All Cohorts: 
o AE monitoring. 
o Concomitant medication monitoring. 
 Cohort 1, 2, and 3: 
o PK blood samples will be collected using a window approach at 24 to 36 hours 
postdose. 
o PD blood samples for estimation of biomarkers of coagulation (aPTT, PT, and 
anti-FXa) immediately after collection of the simultaneously scheduled PK 
samples at 24 to 36 hours postdose. 
 Cohort 4: 
o PK blood samples will be collected using a window approach at 24 to 36 hours 
postdose. 
 Cohort 5: 
o Note: For this cohort, only 3 of 4 possible PK timepoints will provide a blood 
specimen. For patients who provided only 2 PK blood samples on Day 1, a 3rd PK 


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blood sample will be collected at 24 to 36 hours. No PK blood samples will be 
collected for patients who provided 3 PK blood samples on Day 1. 
Note: the overnight stay on Day 1 is not required; however, the above procedures will 
occur on Day 2.  Some patients may be given the option to have a home healthcare 
service conduct the Day 2 procedures in the patient’s home, depending on the availability 
of the service in the patient’s country.  Exact dates and times of dosing and sample 
collection will be recorded in the patients’ CRFs and used for analyses.  At time points 
when PK and PD blood samplings occur at the same time, the PK blood samples will be 
collected first and then PD blood samples will be collected. 
6.3.3.3. 
 
Day 3 
On Day 3, the following procedures will be performed: 
 PK blood samples for Cohort 1: will be collected using a window approach at 48 to 
54 hours postdose. 
 Vital signs (including blood pressure, pulse rate, and body temperature) will be taken 
48 to 54 hours postdose. All vital sign assessments will be performed before the 
scheduled blood sampling for edoxaban and after at least a 5-minute rest in a sitting 
or supine position. The position is which the vital signs are taken (i.e., sitting or 
supine) will be recorded in the CRF. 
 AE monitoring. 
 Concomitant medication monitoring. 
Note: the overnight stay on Day 2 is not required; however, the above procedures will occur on 
Day 3. Some patients may be given the option to have a home healthcare service conduct the 
Day 3 procedures in the patient’s home, depending on the availability of the service in the 
patient’s country. Exact dates and times of dosing and sample collection will be recorded in the 
patients’ CRFs, and used for analyses.  
6.4. 
Follow-up  
Patients will participate in a follow-up visit.  The visit will occur within 10 days after the 
edoxaban dosing.  It will include the following: 
 All Cohorts: 
o Physical examination, including weight, BMI, and height. 
o Vital signs including blood pressure, pulse rate, and body temperature after 
resting at least 5 minutes in a sitting or supine position (Note: the appropriate cuff 
size based on arm circumference will be used.) 
o AE monitoring. 
o Concomitant medication monitoring. 
o Coagulation (PT, INR, and aPTT). 
o Blood samples for clinical laboratory tests (hematology) (refer to Section 9.6). 


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 Cohorts 1, 2, and 3: 
o Blood samples for clinical laboratory tests (serum chemistry) (refer to 
Section 9.6). 
Some patients may be given the option to have a home healthcare service conduct follow-up 
procedures in the patient’s home, depending on the availability of the service in the patient’s 
country. 
6.5. 
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 IRB/IEC. 
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 patient.  Sponsor must be 
notified of all intended or unintended deviations to the protocol (e.g., 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 patient was ineligible or received the incorrect dose or investigational treatment, and had at 
least 1 administration of IP, data should be collected for safety purposes. 
The Investigator should notify the IEC or IRB of deviations from the protocol in accordance with 
local procedures. 


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7. 
EFFICACY ASSESSMENTS 
Not applicable. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic Variable(s) 
8.1.1. 
Collection of Samples 
PK blood samples will be collected for measurement of plasma concentrations of edoxaban and 
its metabolites (D21-2393, D21-3231, D21-1402, and D21-2135).   
PK blood samples for patients in Cohort 1: Serial PK blood samples (2 mL per sample) will 
be collected over the following time windows: 
 0.25 to 1 hour postdose (1 sample) 
 1.5 to 3 hours postdose (1 sample) 
 3.5 to 6 hours postdose (1 sample) 
 6.5 to 8 hours postdose (1 sample) 
 8.5 to 14 hours postdose (1 sample) 
 24 to 36 hours postdose (1 sample) 
 48 to 54 hours postdose (1 sample) 
PK blood samples for patients in Cohort 2 and 3: Serial PK blood samples (patients 6 to 
< 12 years of age: 2 mL per sample and patients < 6 years of age: 1 mL per sample) will be 
collected over the following time windows: 
 0.25 to 1 hour postdose (1 sample) 
 1.5 to 3 hours postdose (1 sample) 
 4 to 8 hours postdose (1 sample) 
 9 to 14 hours postdose (1 sample) 
 24 to 36 hours postdose (1 sample) 
PK blood samples for patients in Cohort 4: Serial PK blood samples (600 µL per sample) will 
be collected over the following time windows: 
 0.5 to 2 hours postdose (1 sample) 
 3 to 8 hours postdose (1 sample) 
 9 to 14 hours postdose (1 sample) 
 24 to 36 hours postdose (1 sample) 


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PK blood samples for patients in Cohort 5: PK blood samples (600 µL per sample) will be 
collected after edoxaban administration at a total of 3 of the 4 possible timepoints postdose 
(timepoints will be assigned by the Sponsor once the subject is approved to be randomized): 
 0.5 to 2 hours postdose (mandatory) (1 sample) 
 3 to 8 hours postdose (1 sample) 
 9 to 14 hours postdose (1 sample) 
 24 to 36 hours postdose (1 sample) 
Emerging PK concentration-time data from completing patients will be analyzed on an ongoing 
basis and used to refine and optimize the PK blood sampling scheme (i.e., both the number of 
samples and the sampling windows) if necessary.  
The total blood volume collected for each age cohort will not exceed the guidelines for pediatrics 
research for each age cohort.9 Blood loss must not exceed 1% of total blood volume at any time, 
3% during 4 weeks. Blood sampling from patients for bioanalytical assessment will use the local 
methods appropriate for the patient’s age to minimize associated blood volume, invasiveness, 
and pain. 
Exact dates and times of dosing and sample collection will be recorded in the patients’ CRFs and 
used for analyses. 
Samples will be collected, labeled, stored, and shipped as detailed in Appendix 17.2. 
8.1.2. 
Determination of Drug Concentrations 
The plasma samples will be assayed for edoxaban and metabolites using a validated LC-MS/MS 
assay. 
Edoxaban and D21-2393 will be evaluated for each time point, and if sufficient sample volume is 
available, then the following metabolites will also be assessed at each time point: D21-3231, 
D21-1402, and D21-2135.  If sufficient blood volume is not available, then blood samples for a 
patient will be analyzed for edoxaban and D21-2393 for each time point but pooled to analyze 
the pooled sample for analysis of other metabolites.  The pooled sample will also be analyzed for 
edoxaban and D21-2393, so relative abundance of metabolites to edoxaban can be calculated. 
8.1.3. 
Rationale for Sample Collection Scheme  
Blood sampling times specified in Section 8.1.1 have been optimized based on PopPK and 
simulations, as described in Section 1.3. 
8.2. 
Pharmacodynamic Variable(s) 
8.2.1. 
Coagulation 
PD blood samples for patients in Cohort 1:  Serial PD blood samples (1.8 mL per sample 
[Aliquots 1 and 2 will have approximately 0.25 mL and Aliquot 3 will hold the remaining 
portion of the sample]) will be collected (concurrent with the PK blood samples, if applicable) 
for measurement of biomarkers of coagulation (aPTT, PT, and anti-FXa) over the following time 
windows: 


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 Predose (1 sample) 
 0.25 to 1 hour postdose (1 sample) 
 1.5 to 3 hours postdose (1 sample) 
 3.5 to 6 hours postdose (1 sample) 
 6.5 to 8 hours postdose (1 sample) 
 24 to 36 hours postdose (1 sample) 
PD blood samples for patients in Cohort 2 and 3: Serial PD blood samples (patients 6 to 
< 12 years of age: 1.8 mL per sample and patients < 6 years of age: 1 mL per sample [Aliquots 1 
and 2 will have approximately 0.25 mL and Aliquot 3 will hold the remaining portion of the 
sample]) will be collected (concurrent with the PK blood samples, if applicable) for 
measurement of biomarkers of coagulation (aPTT, PT, and anti-FXa) over the following time 
windows: 
 Predose (1 sample) 
 0.25 to 1 hour postdose (1 sample) 
 1.5 to 3 hours postdose (1 sample) 
 4 to 8 hours postdose (1 sample) 
 9 to 14 hours postdose (1 sample) 
 24 to 36 hours postdose (1 sample) 
PD blood samples for patients in Cohort 4 and 5: PD blood samples (1 mL per sample 
[Aliquots 1 and 2 will have approximately 0.25 mL and Aliquot 3 will hold the remaining 
portion of the sample]) will be collected (concurrent with the PK blood samples, if applicable) 
for measurement of biomarkers of coagulation (aPTT, PT, and anti-FXa) over the following time 
windows: 
 Screening Visit (1 sample) 
 0.5 to 2 hours postdose (1 sample) 
The total blood volume collected for each age cohort will not exceed the guidelines for pediatrics 
research for each age cohort.9 Blood loss must not exceed 1% of total blood volume at any time, 
3% during 4 weeks. For younger age cohorts, microsampling assays may be employed.  Blood 
sampling from patients for PD assessment will use the local methods appropriate for the patient’s 
age to minimize associated blood volume, invasiveness, and pain. 
Exact dates and times of dosing and sample collection will be recorded in the patients’ CRFs and 
used for analyses. 
Samples will be collected, labeled, stored, and shipped as detailed in Appendix 17.2. 
8.3. 
Biomarker and Exploratory Variable(s) 
Not applicable. 


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9. 
SAFETY ASSESSMENTS 
9.1. 
Adverse Events 
All clinical AEs occurring after the patient (or parent/guardian) signs the ICF and through the 
follow-up visit (up to 10 days after the last dose), whether observed by the Investigator or 
reported by the patient or patient’s parent/guardian, will be recorded on the AE 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 SAEs are to be reported according to the procedures in Section 9.4 SAE 
Reporting-Procedure for Investigators.  Investigator diagnosis will be recorded.  Always report a 
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 which do not worsen in severity 
should not be reported as SAEs (see Section 9.3.2 for definitions).  For deaths, the underlying or 
immediate cause of death should always be reported as an SAE.  In addition, 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. 
Each day the Investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient (or 
parent/guardian) or by questioning the patient at each study visit.  Patients should be questioned 
in a general way, without asking about the occurrence of any specific symptoms.  All laboratory 
values must be appraised by the Investigator as to clinical significance.  All abnormal laboratory 
values considered clinically significant by the Investigator must be recorded as an AE on the 
CRF, and if serious, reported as an SAE following the procedures in Section 9.4. 
The Investigator should follow patients with AEs until the event has resolved or the condition 
has stabilized.  In case of unresolved AEs including significant abnormal laboratory values at the 
end of study assessment, these events will be followed up until resolution or until they become 
clinically not relevant. 
9.2. 
Safety Endpoints 
Not applicable.   
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended 


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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 lab findings which should be considered AEs. 
9.3.2. 
Serious Adverse Event  
Any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient 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 patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  Examples 
include allergic bronchospasm, convulsions, blood dyscrasias, or development of drug 
dependency or drug abuse. 
Note: 
 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 treatment requiring 
hospitalizations for pre-existing conditions which do not worsen in severity are not 
SAEs. 
9.3.3. 
Adverse Event Severity 
The following definitions should be used to assess intensity of AEs: 
 Mild: Awareness of sign or symptom, but easily tolerated, i.e., does not interfere with 
patient’s usual function. 
 Moderate: Discomfort enough to cause interference with usual activity. 


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 Severe: Incapacitating with inability to work or do usual activity, i.e., interferes 
significantly with patient’s usual function. 
9.3.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the IP on the basis or 
his/her clinical judgment and the following definitions.  The causality assessment should be 
made based on the available information and can be updated as new information becomes 
available. 
 1 = Related: 
 The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the patient’s clinical state or other factors 
(e.g., disease under study, concurrent diseases, and concomitant medications). 
 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. 
 2 = Not Related: 
 The AE does not follow a reasonable sequence from study product administration 
or can be reasonably explained by the patient’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, and concomitant medications). 
9.3.5. 
Action Taken Regarding the Study Product 
 1 = Dose Not Changed: No change in study drug dosage was made. 
 2 = Drug Withdrawn: The study product was permanently stopped. 
 3 = Dose Reduced: The dosage of study product was reduced. 
 4 = Drug Interrupted: The study product was temporarily stopped. 
 5 = Dose Increased: The dosage of study product was increased. 
9.3.6. 
Adverse Event Outcome 
 1 = Recovered/Resolved 
 The patient fully recovered from the AE with no residual effect observed. 
 2 = Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 3 = Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 4 = Fatal 
 5 = Unknown 


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9.3.7. 
Other Action Taken for Event 
 1 = None 
 No treatment was required. 
 2 = Medication required 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 3 = Other 
9.4. 
Serious Adverse Event Reporting – Procedure for Investigators 
9.4.1. 
Initial Reports 
Within 24 hours of receipt of an SAE report: 
 Complete a Daiichi Sankyo SAVER form, sign it, and fax it to Medpace using the 
designated fax transmittal form.  Medpace will review and forward the SAVER form 
to Daiichi Sankyo Clinical Safety and Pharmacovigilance (CSPV). 
 Call the Medpace SAE hotline for any questions regarding SAE reporting.   
Medpace SAE hotline – USA 
 
Medpace SAE hotline – Europe: 
 
 Place the initial version of SAVER in the patient’s file. 
9.4.2. 
Follow-up Reports 
Within 24 hours of the receipt of new information for a reported SAE: 
 Complete a Daiichi Sankyo SAVER form with the new information.  Please complete 
Sections 1 through 3 even if they contain no new information.  For Sections 4 through 
10, provide only the new information.  Sign and fax the form to Medpace using the 
fax transmittal form. 
 For SAEs that resulted in death, provide the autopsy report, if available, via e-mail, 
fax, or express mail. 
 The CRO designated above will review and forward the follow-up SAVER form and 
supporting documents to Daiichi Sankyo CSPV. 
 Place the follow-up version of the SAVER form and all supporting documentation in 
the patient’s file. 
PPD
PPD


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9.4.3. 
Notifying Regulatory Authorities, Investigators, and IRB/IEC 
Daiichi Sankyo and/or Medpace will inform Investigators, IRBs/IECs, and regulatory authorities 
of any Suspected Unexpected SAE Reactions (SUSARs) occurring in other clinics or other 
Daiichi Sankyo studies of the IP, as appropriate per local reporting requirements. 
In the United States, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
IP, 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 
IECs. 
The Reference Safety Information for the study is found in Section 6.11 of the Investigator’s 
Brochure. 
9.5. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any patient who becomes pregnant while receiving the IP or 
during the follow-up period. 
Although pregnancy is not technically an AE, 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 patient using the Exposure In Utero (EIU) Reporting form.  Please make sure the patient 
does not receive any study drug after learning of the pregnancy and contact your study monitor 
to receive the EIU Reporting Form upon learning of a pregnancy.  The Investigator should make 
every effort to follow the patient until completion of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (i.e., post-partum 
complications, spontaneous 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 9.4. 
9.6. 
Clinical Laboratory Evaluations 
Blood samples for the following hematology tests will be taken at screening (if not performed 
within 2 weeks prior to screening) and at the final follow-up visit (or early termination).  Blood 
samples for the following serum chemistry tests will be taken at screening (if not performed 
within 2 weeks prior to screening) for all cohorts, and at the final follow-up visit (or early 
termination) for Cohorts 1, 2, and 3. Cohorts 4 and 5 will not have serum chemistry performed at 
the final follow-up (or early termination) visit. (See Appendix Section 17.7). 
 Hematology: hemoglobin, hematocrit, red blood cell (RBC) count (with indices), 
reticulocyte count, white blood cell (WBC) count (with differential), and platelet 
count 
 Serum chemistry: sodium, potassium, magnesium, bicarbonate, chloride, calcium, 
AST, ALT, alkaline phosphatase, total bilirubin, lactate dehydrogenase, glucose, 
creatinine, blood urea nitrogen, total protein, albumin, uric acid, creatine kinase, total 
cholesterol, and triglycerides 


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Urinalysis to include urine dipstick with specific gravity, pH, protein, glucose, ketones, blood, 
RBC, WBC, bilirubin, and urobilinogen at screening and check-in. Microscopic analysis is 
required if dipstick is positive for blood, RBC, or WBC. 
At screening only, blood will be collected for hematology and serum chemistry (if not performed 
within 2 weeks prior to screening) to include blood volume for HIV and hepatitis B and C 
testing.  A pregnancy test (based on local practice) will be performed at screening and at 
check-in (Day -1/1 predose) for all female patients who have had menarche.  At screening, urine 
samples will also be used to check for the presence of the following controlled substances: 
opiates, benzodiazepines, amphetamines, cannabinoids, cocaine, barbiturates, phencyclidine, 
cotinine levels (non-exclusionary), and alcohol. 
Coagulation tests (PT, INR, and aPTT) will be collected in citrated blood collection tubes during 
screening and at the follow-up visit.  Blood samples will be treated for PT, INR, and aPTT 
estimation as per the SOPs of the local or central laboratory. 
The blood volume for all scheduled clinical laboratory assessments will not exceed the 
guidelines for pediatrics research for each age cohort.9 Blood loss must not exceed 1% of total 
blood volume at any time, 3% during 4 weeks.  
9.7. 
Vital Signs 
Vital signs (blood pressure, pulse rate, and body temperature) will be monitored at screening, at 
check-in (Day -1/Day 1 predose), Day 1 (and Day 3 for patients enrolled prior to Version 5.0 of 
the protocol) postdose, and at the final follow-up visit (or early termination).  Heart rate and 
blood pressure will be measured after an at least 5-minute rest in a sitting or supine position.  
The position in which the vital signs are measured will be recorded in the patients’ CRF. 
9.8. 
Electrocardiograms  
Not applicable. 
9.9. 
Physical Findings 
A complete physical examination will be performed on each patient at screening, at check-in 
(Day -1/Day 1 predose), on Day 3 (for patients enrolled prior to Version 5.0 of the protocol), and 
during the follow-up visit. 
Body height and weight will be measured for all patients during the physical examinations to 
determine BMI. 
9.10. 
Other Safety Assessments 
Not applicable. 


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10. 
OTHER ASSESSMENTS 
Formulation Palatability 
Patients receiving the edoxaban granule for oral suspension formulation who are 
developmentally capable of providing an accurate response will be asked to rate several aspects 
of palatability (including bitterness, sweetness, overall taste, and aroma) using 100 mm VAS. 
The VAS questionnaire will be provided to the sites by Medpace. 
Patients who are old enough will score the VAS themselves.  For younger children, the parents 
will provide this information, if possible.  For the youngest children, there will be free text input 
available, to provide information on whether the patient spit it out and may not have liked the 
flavor, etc. 
VAS and text responses will be measured and/or recorded on the CRF.  Refer to Appendix 17.6 
for the VAS. 


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11. 
STATISTICAL METHODS 
11.1. 
Analysis Sets 
11.1.1. 
Pharmacokinetic Analysis Set 
The PK analysis set will comprise all patients who receive edoxaban as per protocol and have at 
least 1 postdose PK measurement with known collection times and date/time of dose 
administration and who do not have any clinically significant events or protocol deviations that 
may have compromised the integrity of the PK results. 
11.1.2. 
Pharmacodynamic Analysis Set 
The PD analysis set will comprise all patients who receive edoxaban as per protocol and have at 
least 1 postdose PD measurement with known collection time and date/time of dose 
administration and who do not have any clinically significant events or protocol deviations that 
may have compromised the integrity of the PD results. 
11.1.3. 
Safety Analysis Set 
The safety analysis set will include all patients who received edoxaban. 
11.2. 
General Statistical Considerations 
Complete details of the planned statistical analyses will be included in a separate Statistical 
Analysis Plan.  The analyses for this study will be considered descriptive and exploratory.  No 
visit windows will be used for analysis. 
In general, all data will be summarized by age cohort and dose group, and all evaluable data will 
be included in the analyses.  For qualitative variables, the population size (N for sample size and 
n for available data) and the percentage/incidence (of available data) for each class of the 
variable will be presented.  Quantitative variables will be summarized using descriptive statistics, 
including the population size (N for sample size and n for available data), mean, SD, coefficient 
of variation (CV%), median, minimum, and maximum values. 
11.3. 
Study Population Data 
Patient disposition, demographics and baseline characteristics, prior and concomitant 
medications will be tabulated. 
11.4. 
Efficacy Analyses 
Not applicable. 


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11.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
11.5.1. 
Pharmacokinetic Analyses 
Plasma concentration-time data for edoxaban and metabolites (if data are available) will be listed 
by patient, age cohort and/or dose group, and measurement time interval, and will be plotted and 
summarized using descriptive statistics, as appropriate. 
Plasma concentration-time data for edoxaban and metabolites will be analyzed using 
model-based approaches such as nonlinear mixed effects modeling, where data from other 
studies may be pooled with pediatric data, and PK parameters will be calculated.  The goal of 
this approach will be to estimate PK parameters such as CL/F and V/F in pediatric patients.  
Derived PK parameters such as AUC and metabolite-to-parent ratios (if data permit) for AUC 
will also be estimated.  Estimated PK parameters will be assessed for age dependencies using 
graphical and/or modeling methods.  Estimated PK parameters will be listed and summarized by 
age cohort and/or dose group using descriptive statistics. 
An exploratory analysis of variance model will be applied to natural log-transformed CL/F, V/F, 
and AUC with age cohort, dose, and age cohort by dose interaction as fixed factors.  Appropriate 
adjustments on parameters, e.g., dose-normalization on AUC, or body weight-normalization on 
CL/F and V/F, might also be explored.  The least-squares mean differences between age cohorts 
with age cohort of 12 to < 18 years as the reference and the corresponding 95% confidence 
intervals (CIs) will be exponentiated to obtain point estimates of ratios of geometric means and 
the corresponding 95% CIs by dose level and/or overall (as appropriate). 
11.5.2. 
Pharmacodynamic Analyses 
For PD biomarkers (PT, aPTT, and anti-FXa), observed, change-from-baseline, and percent-
change-from-baseline data will be listed by patient, age cohort and/or dose group, and 
measurement time interval, and will be plotted and summarized using descriptive statistics, as 
appropriate. 
The PK/PD relationships will be examined graphically to assess age dependencies.  Additional 
PK/PD modeling may be conducted, if necessary, to understand age dependencies. 
11.6. 
Safety Analyses 
All analyses involving safety data (physical examination, vital signs, AEs, clinical laboratory 
tests [hematology, serum chemistry, and urinalysis]) will be based on the safety analysis set. 
11.6.1. 
Adverse Event Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary (latest version).  All AEs, including SAEs, will be mapped to system organ 
class and preferred term and will be listed in the data listing.  A TEAE is defined as an AE that 
emerges during treatment, having been absent pretreatment, or worsening relative to the 
pretreatment state.  The number and percentage of patients reporting TEAEs will be tabulated for 
the safety analysis set by MedDRA preferred term and system organ class with a breakdown by 
dose, and further by relationship to study drug administered, and by severity.  Listings of death 
events, SAEs, and AEs that lead to discontinuation of a patient will be presented. 


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11.6.2. 
Clinical Laboratory Evaluation Analyses 
Standard hematology, serum chemistry, coagulation, and urinalysis at each planned assessment 
and change from baseline at each planned post-baseline assessment will be summarized for the 
safety analysis set by dose.  Patients with abnormal values will be noted in the data listings. 
11.6.3. 
Vital Sign Analyses 
Vital signs will be summarized using descriptive statistics for baseline, each study evaluation, 
and change from baseline to each evaluation.  Listings of all vital sign data will be provided. 
11.6.4. 
Physical Finding Analyses 
Results of physical examinations conducted throughout the study will be presented in listings.  
Patients with clinically significant abnormal findings will be noted in the data listings. 
11.7. 
Other Analyses 
11.7.1. 
Palatability Analyses 
The VAS scores for palatability will be listed and summarized by age cohort and/or dose group 
using descriptive statistics, if data permit. 
11.8. 
Interim Analyses 
Emerging PK concentration-time data from completing patients will be analyzed using 
model-based approaches on an ongoing basis and used to predict and optimize the doses required 
to obtain targeted exposures in upcoming age cohorts and dose groups.  Additionally, this 
ongoing PK analysis will be used to refine and optimize the PK blood sampling scheme (number 
of samples and timing) in upcoming age cohorts and dose groups. 
11.9. 
Data and Safety Monitoring Board 
An independent DSMB consisting of a panel of clinicians or therapeutic area experts will be 
convened to provide independent review to assure that patient safety and integrity of the trial are 
being upheld. Responsibilities of the DSMB are set forth in the DSMB Charter. 
11.10. 
Sample Size Determination 
A total of 60 patients will be enrolled, 12 evaluable per age cohort.  Based on the assumptions of 
the inter-patient CV of 10.8% and 29.3% for CL/F and V/F respectively10, and the ratio of a 
younger age cohort to the reference age cohort (12 to < 18 years) to be 1, a sample size of 
12 evaluable per age cohort would provide > 95% power to assess that the 95% CI for cohort to 
reference cohort ratio is contained within the 60% to 140% range for CL/F.  This sample size 
would provide about 76% power for the assessment on V/F.  If emerging data suggest that the 
variability is much larger than anticipated, sample size may be increased. 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspections by providing direct access to source data/documents.  Direct 
access includes permission to examine, analyze, verify, and reproduce any records and reports 
that are important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The DSI 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 (e.g., CRFs, source data, and other pertinent documents). 
The monitor is responsible for visiting site(s) at regular intervals throughout the study to verify 
adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to 
ICH GCP and local regulations on the conduct of clinical research.  The monitor is responsible 
for inspecting the CRFs and ensuring completeness of the study essential documents.  The 
monitor should have access to patient medical records and other study-related records needed to 
verify the entries on the CRFs. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action 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 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.  Inspection of site facilities (e.g., pharmacy, drug storage 
areas, laboratories, etc.) 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. 
12.2. 
Data Collection 
Completion of the CRFs should be kept current to enable the monitor to review the patient’s 
status throughout the course of the study.  The CRF will be completed, reviewed, and signed off 
or e-signed by the Investigator. 
If the study employs paper CRFs, the Investigator will sign and date the indicated places on the 
CRF.  These signatures will indicate that the Investigator inspected or reviewed the data on the 
CRF, the data queries, and the site notifications, and agrees with the content. 
If the study employs Electronic Data Capture, the Investigator e-signs according to the study data 
flow. 


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12.3. 
Data Management 
Each patient will be identified in the database by a unique patient identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all patients and sites, a Clinical Data Management 
review will be performed on patient data according to specifications given to DSI.  Data will be 
vetted both electronically and manually.  For electronic CRFs, 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 Electronic Data Capture application.  During this 
review, patient data will be checked for consistency, omissions, and any apparent discrepancies. 
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using the most current version of MedDRA. 
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 
CRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the patient’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. 
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: 
 Patient files containing completed CRFs, informed consents, 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 IEC/IRB and the Sponsor. 
 Records related to the IP(s) including acknowledgment of receipt at 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 Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have lapsed since the 
formal discontinuation of clinical development of the IP.  These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by an 


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agreement with the Sponsor.  It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
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. 
12.5. 
Record Keeping 
Records of patients, source documents, monitoring visit logs, data correction forms, CRFs, 
inventory of study product, regulatory documents (e.g., protocol and amendments, IRB/IEC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, and distribution and return records), and other Sponsor correspondence 
pertaining to the study must be kept in appropriate study files at the site.  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 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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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 DSI.  This agreement will include the financial information agreed upon by the 
parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
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. 
STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the Investigator by the Sponsor.  All protocol amendments will undergo the 
same review and approval process as the original protocol.  A protocol amendment may be 
implemented after it has been approved by the IRB/IEC, unless immediate implementation of the 
change is necessary for patient safety.  In this case, the situation must be documented and 
reported to the IRB/IEC within 5 working days.  The Sponsor will assure the timely submission 
of amendments to regulatory authorities. 
15.2. 
Address List 
15.2.1. 
Sponsor 
Daiichi Sankyo, Inc. 
211 Mount Airy Rd 
Basking Ridge NJ 07920 
15.2.1.1. Daiichi Sankyo, Inc. Medical Monitor 
  
Daiichi Sankyo, Inc. 
211 Mount Airy Rd 
Basking Ridge, NJ 07920 
15.2.1.2. Clinical Study Leader 
  
Daiichi Sankyo, Inc. 
211 Mount Airy Rd 
Basking Ridge  NJ 07920 
 
15.2.1.3. Daiichi Sankyo, Inc. Clinical Study Manager 
 
Clinical Development Operations 
Daiichi Sankyo, Inc. 
211 Mount Airy Rd 
Basking Ridge, NJ 07920 
PPD
PPD
PPD
PPD
PPD
PPD


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Clinical Development Operations 
Daiichi Sankyo, Inc. 
211 Mount Airy Rd 
Basking Ridge, NJ 07920 
15.2.2. 
Clinical Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
15.2.2.1. Clinical Research Organization Medical Monitor 
  
Senior Medical Director 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
Home office:  
Wester Bogaardstraat 2 
2011 WX Haarlem 
the Netherlands 
15.2.2.2. Clinical Research Organization Project Manager 
Global Clinical Trial Manager 
 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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15.2.3. 
Drug Safety 
15.2.3.1. Sponsor Serious Adverse Event Report Form General Contact  
Daiichi Sankyo, Inc. 
Clinical Safety and Pharmacovigilance 
 
15.2.4. 
Data Management 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
15.2.5. 
Biological Pharmacokinetic Specimens  
 or delegate 
Q2 Solutions 
19 Brown Rd 
Ithaca, NY 14850 
15.2.6. 
Biological Pharmacodynamic Specimens 
 
Project Coordinator 
Medpace Reference Laboratories, United States 
5365 Medpace Way 
Cincinnati, OH 45227 
15.2.7. 
Biological Specimens (Outside North America Only) 
 
Project Manager 
Medpace Reference Laboratories, Belgium 
Technologielaan 19 
3001 Leuven, Belgium 
15.2.8. 
Clinical Safety Laboratory 
Central or local laboratories.  
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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16. 
REFERENCES 
1. DU-176b Investigator’s Brochure, November 2013. 
2. Chen N, Aleksa K, Woodland C, Rieder M, Koren G. Ontogeny of drug elimination by 
the human kidney. Pediatr Nephrol 2006; 21: 160-168. 
3. De Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny 
and drug disposition. Clin Pharmacokinet 1999; 37: 485-505. 
4. Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in 
infants. Part 1. Clin Pharmacokinet 2002; 41: 959-998. 
5. Abdel-Rahman SM, Amidon GL, Kaul A, Lukacova V, Vinks AA, Knipp GT et al. 
Summary of the National Institute of Child Healthy and Human Development – Best 
Pharmaceuticals for Children Act pediatric formulation initiatives workshop – pediatric 
biopharmaceutics classification system working group. Clin Therap 2012; 34: S11-24. 
6. Novak M, Schlagenhauf A, Bernhard H, Schweintzger S, Leschnik B, and Muntean W. 
Effect of rivaroxaban, in contrast to heparin, is similar in neonatal and adult plasma. 
Blood Coag Fibrinolysis 2011, 22:588-592. 
7. 2000 CDC (Centers for Disease Control and Prevention) Growth charts for the United 
States: Methods and Development. [Internet]. May 2002 [cited 2013 Aug 28]; 11(246). 
Available from: http://www.cdc.gov/growthcharts/2000growthchart-us.pdf. 
8. Schwartz GJ, Work DF. Measurement and Estimation of GFR in Children and 
Adolescents. Clin J Am Soc Nephrol 2009; 4: 1832-43. 
9. Howie SRC. Blood sample volumes in child health research: review of safe limits. 
Bulletin of WHO. 2011; 89: 46-53. 
10. TMPP 006, Edoxaban Population Pharmacokinetic Analysis Based on Phase 1 Data, 
4 Feb 2013. 
11. Young G, Albisetti M, Bonduel M et al. Impact of inherited thrombophilia on venous 
thromboembolism in children. Circulation. 2008;118:1373-82. 
12. Young G. New anticoagulants in children. Hematology Am Soc Hematol Educ Program. 
2008:245-50. 


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17. 
APPENDICES 
17.1. 
Additional Information on Investigational Products 
Edoxaban 15 mg, 30 mg, and 60 mg tablets contain mannitol, pregelatinized starch, 
crospovidone, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium dioxide, 
talc, polyethylene glycol, iron oxide yellow, iron oxide red (15 mg orange film-coated tablets 
only), and carnauba wax. 
Edoxaban granules for oral suspension 60 mg contains mannitol, pregelatinized starch, 
crospovidone, hydroxypropyl cellulose, carboxymethylcellulose sodium, xylitol, and strawberry 
flavor. 


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17.2. 
Instructions for Specimen Collection, Storage, and Shipment 
17.2.1. 
Collection, Storage, Handling, and Shipping for Sample Analysis of Plasma 
Edoxaban (DU-176b) and Metabolites 
A blood volume not to exceed the guidelines for pediatrics research for each age cohort9 will be 
taken from specified patients at the times detailed in Section Section 8. Blood loss must not 
exceed 1% of total blood volume at any time, 3% during 4 weeks. Blood sampling from patients 
for bioanalytical assessment will use the local methods appropriate for the patient’s age to 
minimize associated blood volume, invasiveness, and pain.  
 If 1.0 to 2.0 mL of blood, in accordance to volume guidance described above, can be 
collected for the specified time points, the following procedures can be applied:  
blood samples will be collected into pre-chilled 2 mL polyethylene Vacutainer tubes 
containing lithium heparin as anticoagulant for the preparation of plasma. 
 For Cohorts 1 to 3, if less than 1.0 mL of blood can be collected following volume 
guidance described above, small volume blood collection procedures and devices, 
deemed age-appropriate locally for collecting lithium heparin plasma can be applied.  
It is important to ensure that such procedures should not introduce volume bias, i.e., 
no pre- or post-addition of any solution to the blood collection tube (which may affect 
the volume of harvested plasma).  Recommended devices, and collection procedures, 
are described in lab manual. 
The tube containing blood for plasma preparation will be gently inverted multiple times ( 8) to 
ensure thorough mixing of anticoagulant (lithium heparin) and blood, then placed in a cool box 
containing ice/water mixture.  The samples should be centrifuged within 45 minutes of 
collection, at approximately 1,500 g for approximately 10 minutes.  Immediately following 
centrifugation, the separated plasma should be pipetted (be careful not to touch the bottom layer), 
into sample storage vial(s) following the below suggestion: 
 If more than approximately 0.3 mL of plasma is harvested, the plasma will be divided 
approximately equally into 2 polypropylene cryogenic sample storage vials 
(designated Aliquot 1 and 2) with screw-cap. The sample storage vial volume should 
not exceed 2.0 mL. Each storage vial should contain more than 100 µL of plasma. 
 For Cohorts 1 to 3, if less than approximately 0.3 mL of plasma is harvested, then the 
plasma will be transferred into 1 polypropylene cryogenic sample storage vial 
(designated Aliquot 1) with screw-cap. The sample storage vial volume should not 
exceed 2.0 mL. 
The cryogenic vials should be maintained by being chilled on ice before transferred to the 
freezer.  Within 90 minutes after blood draw, the sample storage vials will be stored, still in 
upright position, in the dark in a non-cycling freezer at approximately -20ºC  10oC.   
Any sample anomalies should be recorded on the sampling forms. 
Sample Transfer 
Samples will be shipped to a central lab.  For international shipment, a courier that can monitor 
and replenish dry ice should be used.  Each country should establish its own process for 


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monitoring and replenishing dry ice.  Shipments will be sent after PK samples are collected for 
each patient.  Aliquots 1 and 2 should be shipped on different days.  Samples will be packed in 
sufficient dry ice to last 3 or more days.  Samples should only be shipped on Monday, Tuesday, 
or Wednesday.   
Shipping Documentation 
The shipping documentation should include, at minimum, the following information: 
 Study protocol number 
 Complete inventory of samples shipped 
 Name of shipping site contact person 
Sample Packing Suggestions 
Package samples in appropriate boxes with covers (e.g., fiberboard storage boxes and dividers).  
Secure the covers with rubber bands or tape and identify the contents of each box.  Place boxes 
in a moisture protective bag such as a “SAF-T-PAK” (http://www.saftpak.com) before placing in 
the main shipping carton.  The main shipping carton should consist of a corrugated cardboard 
box with a separate polyfoam box with lid placed inside.  Place the appropriate amount of dry ice 
in the polyfoam box surrounding the sample packages, such that dry ice will last approximately 
3 days. 
Sample Receiving Contact at Q2 Solutions 
or delegate 
Attn: Sample Receiving 
Q2 Solutions 
19 Brown Rd 
Ithaca, NY 14850 
PPD
PPD


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17.2.2. 
Collection, Storage, Handling, and Shipping of Blood Samples for 
Pharmacodynamic Analysis 
The following assays will be made for PD assessments: PT, aPTT, and anti-FXa. 
Blood samples (volumes not to exceed the guidelines for pediatrics research for each age 
cohort9) will be collected in sodium citrated blood collection tubes from specified patients at the 
times detailed in Section 8.  Blood loss must not exceed 1% of total blood volume at any time, 
3% during 4 weeks. Blood sampling from patients for PD assessment will use the local methods 
appropriate for the patient’s age to minimize associated blood volume, invasiveness, and pain.  
For any blood draw, an adequate volume of waste will need to be drawn to clear all tubing of 
tissue debris or possible contaminants (i.e., heparin) as this may impact analyses. All waste may 
be returned to the patient per local hospital practices. Please refer to the Laboratory Manual for 
additional details. 
Immediately after the collection, the samples will be mixed by gentle inversion 8 or more times 
and subsequently within 30 minutes of collection centrifuged at 1,500  g for 15 minutes.  
Samples will then be kept on ice, and the resulting platelet poor plasma (being careful not to 
pipette or disturb cell layer) will then be divided into 3 aliquots (if possible) and transferred to 
clean screw-topped suitably labeled transfer tubes (cryo vials) as follows: 
Aliquots 1 and 2: approximately 0.35 mL per tube 
Aliquot 3: Remainder of the plasma sample into the third tube 
Note – the volumes and the aliquoting scheme might need to be adjusted for each age cohort. 
Aliquot 1 should be shipped first.  After receiving confirmation of receipt, Aliquot 2 and 3 
should be shipped.  All aliquots should be stored at or below -70oC until transferred to Medpace 
for analysis.  Samples should be stored within 60 minutes of collection.  Aliquot 1 will be stored 
in 1 freezer, and Aliquots 2 and 3 will be stored in a different freezer.   
All samples must be packed in sufficient dry ice to last 3 days and will be shipped on a Monday, 
Tuesday, or Wednesday to ensure weekday overnight delivery. 
Samples in North America will be shipped to: 
 
Sample Management 
Medpace Reference Laboratories USA 
5365 Medpace Way 
Cincinnati, OH 45227 
 
PPD
PPD


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Samples outside North America will be shipped to: 
Medpace Reference Laboratories, Belgium 
Technologielaan 19 
3001 Leuven, Belgium 
PPD


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17.3. 
Cytochrome P450 Clinically Significant Drug Interaction Table 
INHIBITORS 
3A4,5,7 
amiodarone 
NOT azithromycin 
cimetidine 
clarithromycin 
diltiazem 
erythromycin 
fluvoxamine 
itraconazole 
ketoconazole 
mibefradil 
nefazodone 
troleandomycin 
verapamil 
INDUCERS 
3A4,5,7 
Carbamazepine 
pioglitazone 
rifabutin 
rifampin 
Troglitazone 
List obtained from P450 Drug Interaction Table: Abbreviated “Clinically Relevant” Table, 
Version 5.0 released on January 12, 2009, last updated on January 31, 2012. Available at:  
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx (last accessed 09 Feb 2012). 


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17.4. 
P-Glycoprotein Inhibitors and Inducers 
Below are examples (but not limited to) the most commonly used P-gp inhibitors: 
17.4.1. 
P-gp Inhibitor Table 
Drug Class 
Drug Name 
Antiarrhythmics 
Amiodarone, quinidine, verapamil, dronedarone, carvedilol, and 
ranolazine 
Antibiotics 
Clarithromycin 
Anti-fungal 
Itraconazole 
Others 
Lapatinib, lopinavir, ritonavir, propafenone, and telaprevir 
17.4.2. 
P-gp Inducers List (Prohibited Medication) 
Rifamin is a P-gp inducer that has been shown to lower the edoxaban exposure. 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 
 Carbamazepin (Tegretol®) 


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17.5. 
Modified Schwartz Equation (Pediatric Patients < 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 


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17.6. 
VAS Patient Questionnaire 
 
 


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Copyright ©2010 American Medical Association. All rights reserved. 
 


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17.7. 
Schedule of Events  
Table 17.1: 
Schedule of Events (All Cohorts) 
Study Day → 
Days -21 
to -2 
Day -1/1 predose 
 
Day 11 
Day 21 
Day 31 
Within 10 days 
after dosing 
Study Hour → 
Screening 
Check-in2 
Predose 
Dosing 
 
 
 
Follow-up3 
Study Event ↓ 
 
 
 
 
 
 
 
 
Informed consent 
(parent/legal guardian) 
X 
 
 
 
 
 
 
 
Assent form (if 
applicable) 
X 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
 
 
 
 
X 
Body weight, height, and 
BMI 
X 
X 
X 
 
 
 
 
X 
Pregnancy test based on 
local practice (for 
post-menarchal females)  
X 
X 
 
 
 
 
 
 
Urine drug screen for 
patients 12 years of age 
and older, for newborns, 
and for patients who are 
being breastfed   
X 
X 
 
 
 
 
 
 
Hematology 
X4 
 
 
 
 
 
X 
Serum chemistry 
X4 
 
 
 
 
 
X5  
Serology 
X4 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
Coagulation (PT, INR, 
and aPTT)6 
X 
 
 
 
 
 
X 
Dosing7 
 
 
 
X 
 
 
 
 
VAS assessment8 
 
 
 
X 
 
 
 
 


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Table 17.1: 
Schedule of Events (All Cohorts) (Continued) 
Study Day → 
Days -21 
to -2 
Day -1/1 predose 
 
Day 11 
Day 21 
Day 31 
Within 10 days 
after dosing 
Study Hour → 
Screening 
Check-in2 
Predose 
Dosing 
 
 
 
Follow-up3 
Study Event ↓ 
 
 
 
 
 
 
 
 
AE/SAE monitoring9 
X 
X 
X 
X 
X 
X 
X9 
X 
Concomitant medication9 
X 
X 
X 
X 
X 
X 
X9 
X 
PK blood draw10 
 
 
 
 
X 
X 
X 
 
PD blood draw10 
X 
 
X 
 
X 
X 
 
 
AE = adverse event; aPTT = activated partial thromboplastin time; BMI = body mass index; INR = international normalization ration; PD = pharmacodynamic; 
PK = pharmacokinetic; PT = prothrombin time; SAE = serious adverse event; SOE = schedule of events; VAS = visual analog scale. 
1. The overnight stay on Day 1 or Day 2 is not mandatory.  The patient may leave the clinic on Day 1 following the completion of all study procedures and 
return to the clinic on Day 2 for the completion of Day 2 procedures (or Day 3 for patients enrolled prior to Version 5.0 of the protocol). Any procedure 
occurring after hour 8 on Day 1 may be performed using a home healthcare service, depending on the availability of the service in the patient’s country. 
2.  Check-in may occur on Day -1 or 1, depending on the site. 
3. Some patients may be given the option to have a home healthcare service conduct the procedures for this visit in the patient’s home, depending on the 
availability of the service in the patient’s country. 
4. Blood samples will be obtained at screening if not drawn within 2 weeks prior to screening. 
5. Serum chemistry will only be obtained from patients in Cohorts 1, 2, and 3. 
6. Only 1 assessment required prior to edoxaban dosing at either screening or upon check-in, as appropriate for the patient. 
7. Doses will be selected based on emerging PK and safety data. 
8. Patients receiving the edoxaban granule for oral suspension formulation who are developmentally capable of providing an accurate response will be asked to 
rate several aspects of palatability (including bitterness, sweetness, overall taste, and aroma) using 100 mm VAS. Patients who are old enough will score the 
VAS themselves. For younger children, the parents will provide this information, if possible. For the youngest children, there will be free text input available 
to provide information on whether the patient spit it out and may not have liked the flavor, etc.  
9. Continuous monitoring after screening procedures are complete. 
10. Refer to cohort-specific PK/PD SOE for specific timepoints. 
 


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Table 17.2: 
Pharmacokinetic and Pharmacodynamic Blood Sampling Schedule for Cohort 1 
Study Day 
→ 
Days -21 
to -2 
Day -1/1 predose 
Day 11 
Day 21 
Day 31 
Within 
10 days 
after dosing 
Study Hour 
→ 
Screening 
Check-in2 
Predose 
0.25-1 hour 
postdose 
1.5-3 hours 
postdose 
3.5-6 hours 
postdose 
6.5-8 hours 
postdose 
8.5-14 hours 
postdose 
24-36 hours 
postdose3 
48-54 hours 
postdose 
Follow-up3 
Blood 
sampling for 
PK4 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Blood 
sampling for 
PD5 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
PD = pharmacodynamic; PK = pharmacokinetic. 
1. The overnight stay on Day 1 or Day 2 is not mandatory.  The patient may leave the clinic on Day 1 following the completion of all study procedures and 
return to the clinic on Day 2 for the completion of Day 2 procedures (or Day 3 for patients enrolled prior to Version 5.0 of the protocol). Any procedure 
occurring after hour 8 on Day 1 may be performed using a home healthcare service, depending on the availability of the service in the patient’s country. 
2. Check-in may occur on Day -1 or 1, depending on the site.  
3. Some patients may be given the option to have a home healthcare service conduct the procedures for this visit in the patient’s home, depending on the 
availability of the service in the patient’s country.  
4. Sampling scheme may be adjusted for various age cohorts based on emerging PK and safety data. The patient will check-out after the last PK sample has 
been collected on Day 3. 
5.  To be concurrent with PK sampling, after PK sampling based on age cohort. 
 


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Table 17.3: 
Pharmacokinetic and Pharmacodynamic Blood Sampling Schedule for Cohorts 2 and 3 
Study Day → 
Days -21 
to -2 
Day -1/1 predose 
Day 11 
Day 21 
Within 10 days 
after dosing 
Study Hour → 
Screening 
Check-in2 
Predose 
0.25-1 hour 
postdose 
1.5-3 hours 
postdose 
4-8 hours 
postdose 
9-14 hours 
postdose 
24-36 hours 
postdose3 
Follow-up3 
Blood sampling 
for PK4 
 
 
 
X 
X 
X 
X 
X 
 
Blood sampling 
for PD5 
 
 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
 
X 
 
X 
PD = pharmacodynamic; PK = pharmacokinetic. 
1. The overnight stay on Day 1 or Day 2 is not mandatory.  The patient may leave the clinic on Day 1 following the completion of all study procedures and 
return to the clinic on Day 2 for the completion of Day 2 procedures. Any procedure occurring after hour 8 on Day 1 may be performed using a home 
healthcare service, depending on the availability of the service in the patient’s country. 
2. Check-in may occur on Day -1 or 1, depending on the site.  
3. Some patients may be given the option to have a home healthcare service conduct the procedures for this visit in the patient’s home, depending on the 
availability of the service in the patient’s country.  
4. Sampling scheme may be adjusted for various age cohorts based on emerging PK and safety data. The patient will check-out after the last PK sample has 
been collected on Day 2. 
5.  To be concurrent with PK sampling, after PK sampling based on age cohort. 
 
 


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Table 17.4: 
Pharmacokinetic and Pharmacodynamic Blood Sampling Schedule for Cohorts 4 and 5 
Study Day → 
Days -21 
to -2 
Day -1/1 predose 
Day 11 
Day 21 
Within 10 days 
after dosing 
Study Hour → 
Screening 
Check-in2 
Predose 
0.5-2 hours 
postdose 
3-8 hours 
postdose 
9-14 hours 
postdose 
24-36 hours 
postdose3 
Follow-up3 
Blood sampling 
for PK4 
 
 
 
X 
X 
X 
X 
 
Blood sampling 
for PD5 
X 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
PD = pharmacodynamic; PK = pharmacokinetic. 
1. The overnight stay on Day 1 or Day 2 is not mandatory.  The patient may leave the clinic on Day 1 following the completion of all study procedures and 
return to the clinic on Day 2 for the completion of Day 2 procedures. Any procedure occurring after hour 8 on Day 1 may be performed using a home 
healthcare service, depending on the availability of the service in the patient’s country. 
2. Check-in may occur on Day -1 or 1, depending on the site.  
3. Some patients may be given the option to have a home healthcare service conduct the procedures for this visit in the patient’s home, depending on the 
availability of the service in the patient’s country.  
4. Sampling scheme may be adjusted for various age cohorts based on emerging PK and safety data. The patient will check-out after the last PK sample has 
been collected on Day 2. Note: Blood is collected at only 3 of the 4 timepoints for Cohort 5; the timepoint 0.5 to 2 hours is mandatory. 
5.  To be concurrent with PK sampling, after PK sampling based on age cohort.