Clinical trial NCT02866175
Conditions: Atrial Fibrillation
Keywords: percutaneous intervention vitamin K antagonist
Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Start date: 2017-02-24; Completion date: 2019-06-06
Enrollment: 1506 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There are insufficient data on the safety and efficacy of edoxaban plus antiplatelet therapy in subjects with atrial fibrillation (AF) following percutaneous intervention (PCI) with stenting. This study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based antithrombotic regimen versus a vitamin K antagonist (VKA)-based antithrombotic regimen in subjects with AF following PCI with stent placement. Bleeding is a central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies and invasive procedures.

Detailed description:

Arms: arm 1: Participants will be randomized to receive edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel \[5 mg or 10 mg once-daily\] or ticagrelor \[90 mg twice-daily\] may be used) used. arm 2: Participants will be randomized to receive VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel \[5mg or 10 mg once-daily\] or ticagrelor \[90 mg twice-daily\] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.
Interventions: intervention 1: Edoxaban intervention 2: Clopidogrel intervention 3: Prasugrel intervention 4: Ticagrelor intervention 5: Vitamin K antagonist
Intervention descriptions: intervention 1: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects intervention 2: Clopidogrel 75 mg once-daily intervention 3: prasugrel 5mg or 10 mg once-daily intervention 4: ticagrelor 90 mg twice-daily intervention 5: VKA once-daily dosing for target international normalized ratio between 2.0 and 3.0, inclusive

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
EVALUATION OF THE SAFETY AND EFFICACY OF AN 
EDOXABAN-BASED COMPARED TO A VITAMIN K 
ANTAGONIST-BASED ANTITHROMBOTIC REGIMEN 
- - F0 bb0 WING-SYGGESFUb- ERGU+ ANEQU S­ 
CORONARY INTERVENTION (PCI) WITH STENT 
PLACEMENT. IBDOXABAN TREATMENT VERSUS 
VKA IN PATIENTS WITH AF UNDERGOING PCI­ 
ENTRUST- AF PCI) 
 
DSE-ED0-01-15-EU 
EudraCT NUMBER 2016-002683-14 
 
VERSION 3.0, 28 FEBRUARY 2017 
 
DAIICHI SANKYO EUROPE GmbH 
ZIELSTATTSTRASSE 48, 81379 MUNICH GERMANY 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is prepared by the authors [European Cardiovascular 
Research Institute (ECRI), Atrial Fibrillation-Network (AF-Net) and DAIICHI SANKYO 
EUROPE GmbH (DSE)] is proprietary to DSE. 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 DSE. 


Protocol DSE-EDO-01-15-EU 
Version 3.0, 28 February 2017 
 
 
INVESTIGATOR AGREEMENT 
Evaluation of the safety and efficacy of an edoxabc1n-based compared to a vitamin K antagonist­ 
based antithrombotic regimen following successful percutaneous coronary intervention (PCI) 
with stent placement. (EDOXABAN TREATMENT VERSUS VKA IN PAIIENTS WITH AF 
UNDERGOING PCI - ENTRUST AF-PCI). 
 
Investigator's Signature: 
 
I have fuliy 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 subject 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 con iderations and guidelines, and to conduct 
the studyin accordance with the Declaration of Helsinki, International Conference on 
Harmonization 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 subjects' 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. 
 
 
 
Date 
Signature 
 
 
 
 
 
 
 
Site no. 
Investigator'sname and address (print or stamp) 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
. 
Page 2 of 114 


 
 
 
 
 
Protocol DSE-EDO-01-15-EU 
Version 3:0, 28 February 2017 
 
Spollijor Appl'oval: 
This clinical study protocol hasbeen re ···ewedand approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSE GmbH, Dlreetor / Safety 
Physlclon Head or Datta Management Group CSP"V, Snfety 
Proj ct Manager & Medical Monitor 
 
 
 
o ,.Global 
 
 
 
 
 
 
 
 
ator 
. 
Study Report 


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PROTOCOL SYNOPSIS 
EudraCT Number: 
2016-002683-14 
Protocol Number: 
DSE-EDO-01-15-EU 
 
  
 
Investig_at_io_n_a_l   
 
Product: 
 
. Active Ingredient(s)/ 
international 
non-proprietary 
name: 
 
 
Study Title.: 
 
E_d_o_x_ab_a_n_'-D-_U_-_1_7_6b_.)'---   - 
- 
  
 
 
 
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/Edoxaban 
Evaluation of the safety and efficacy of an edoxaban-based 
compared to a vitamin K antagonist-based antithrombotic regimen 
following successful percutaneous coronary intervention (PCI) 
with stent placement. IBdoxabaN Treatment vers!!§. VKA in 
pa!ients with AF undergoing PCI ( ENTRUST-AF PCI) 
 
 
 
Study Phase: 
Phase 3b 
 
Indication Under 
Investigation: 
Subjects with atrial fibrillation (AF) following successful PCI 
with stent placement. 
 
 
Study Objectiyes: 
The primary objective is to compare a 12-month antithrombotic 
regimen of edoxaban in combination with clopidogrel or another 
P2Y12 antagonist against a regimen of a vitamin K antagonist 
(VKA) in combination with clopidogrel or another P2Y12 
· antagonist and 1-12 months ASA in subjects with AF following 
successful PCI with stent placement in terms of the incidence of 
major or clinically relevant non-major ISTH-defined bleeding 
(MCRB). 
There are two primary hypotheses for bleeding to be tested 
consecutively in this study. 
• 
The edoxaban-based antithrombotic regimen is non-inferior 
to the VKA-based antithrombotic regimen with regards to 
MCRB. 
• 
The edoxaban-based aritithrombotic regimen is superior to 
the VKA-based antithrombotic regimen with regards to 
MCRB. 


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These two hypotheses are tested in a hierarchical mariner, non-: 
inferiority followed by superiority to control the type-I error rate, 
with adequate power for each of the two hypotheses. 
 
Secondary exploratory objectives of the study are to compare 
  
 
the~edoxaba 
n-basecLant ithrombotic_regimen    to  the  VJ( .A:base "' ------------- ­ 
antithrombotic regimen with regard to: 
• 
Main efficacy endpoint (MEE), defined as the composite of 
cardiovascular (CV) death, stroke, systemic embolic events 
(SEE), spontaneous myocardial infarction (MI) and definite 
stent thrombosis. 
• 
Net clinical benefit (NCB), defined as the composite of CV 
death, stroke, SEE, spontaneous MI, definite stent 
thrombosis and ISTH-defined major bleeding. 
• 
Main thromboembolic event, defined as composite of 
cardiac or thromboembolic death (thromboembolic death 
considered to be thromboembolic in Ofigin (including 
thromboembolic stroke, pulmonary embolism, any other 
systemic embolism), ischemic stroke, SEE, spontaneous MI 
and definite stent thrombosis. 
• 
ISTH-defined major bleeding 
• 
Any bleeding defined as the composite of major, clinically 
relevant non-major and minor bleeding (ISTH definition) 
• 
Symptomatic intracranial hemorrhage (ICH) 
• 
Composite of stroke and SEE 
• 
Composite of all-cause death, stroke, SEE, spontaneous MI 
and definite stent thrombosis 
• 
Composite of CV death, spontaneous MI and definite stent 
thrombosis 
• 
The single components of the composite primary and 
secondary endpoints mentioned above are explored. 
• 
Safety parameters such as (serious) adverse events, 
laboratory parameters, ECG and vital signs. 
 
 
Study Design: 
This is a multinational, multicenter, randomized, open-label Phase 
3b study with blinded evaluation of endpoints by an independent 
  
Clinical Event Committee (CEC) [PROBE design]. An 
 


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independent Data and Safety Monitoring Board (DSMB) is 
responsible for monitoring safety during the study. 
Subjects eligible to participate in the study provide written. 
informed consent (IC) before randomization or any study-specific 
procedures. Once written IC is obtained, subject should be 
randomized without delay via an interactive voice and web 
-,  -   - _re-_sp_on-_se   system (IXRSJ. 
------- 
The Investigator should be prepared to provide subject 
information, including, but not limited to: age, body weight, 
clinical presentation (ACS or stable coronary disease), CrCL using 
Cock.eroft-Gault formula and CKD-EPI Equation for estimating . 
GFR on the Natural Scale (see Section 17.6) and whether the 
subject is taking certain concomitant P-gp inhibitors (see Section 
5.3.1). 
Randomization is stratified by clinical presentation (ACS or stable 
coronary disease), requirement for dose adjustment of edoxaban 
(60 or 30 mg), and geographical region. Subjects are assigned 
randomly via the above mentioned IXRS such that the study has a 
I: I ratio of subjects in the two antithrombotic treatment regimens: 
• 
Edoxaban-based regimen for 12 months: 
1. Edoxaban 60 mg once-daily or 30 mg once-daily in 
selected subjects (see below "Dosage Form, Dose, 
and Route of Administration"and Section 5.3.1). 
2. Clopidogrel 75mg once-daily (or in the presence of 
a documented clinical need prasugrel [5mg _or 10 
mg once-daily] / ticagrelor [90 mg twice-daily] may 
be used). 
The use of a P2Y12 antagonist other than clopidogrel 
must be pre-declared. . 
3. Concomitant use of another anti-platelet agent (i.e. . 
ASA) is not allowed. 
 
• 
VKA-based reg11I1en for 12 months: 
1. The VKA of choice with once-daily dosing for 
target international normalized ratio (INR) between 
2.0 to 3.0, inclusive. 
2. Clopidogrel 75mg once-daily (or in the presence of 
a documented clinical need prasugrel [5mg or 10 
mg once-daily] / ticagrelor [90 mg twice-daily] may 
be used). 


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- 
­ 
 
 
3. ASA (100 mg once-daily) for a minimum of 1 
month and up to 12 months duration at the 
Investigator discretion guided by the clinical 
presentation (ACS or stable coronary disease), and 
upon the CHA2DS2-VASc and HAS-BLED score. 
(1} 
4:·---'-f he  use of a-P2Y12- a ntagonist-other than-clopidogre
1l 
must be pre-declared, together with the intended 
duration of ASA treatment. 
All dosage adjustments are implemented through the IXRS. The 
IXRS provides the appropriate drug supply kit number based on .:-. 
the subject's information as provided by the Investigator. 
 
 
Note: For simplicity, this protocol uses the term "edoxaban" to refer to edoxaban 
tosylate, "clopidogrel" to refer to clopidogrel bisulfate and the term " prasugrel" 
to refer to prasugrel hydrochloride. 
Study Duration: 
 The assigned regimens (edoxaban-based or VKA-based) are 
continued for 12 months and all subjects are followed for 12 
months irrespective of permanent or temporary changes in the 
antithrombotic regimen. Clinical follow-up is only terminated at 
the explicit_docurnented request of the subject. All subjects on 
edoxaban or VKA at 12 mo ths, have a contact planned 30 days 
after the end-of-treatment (EOT) visit, to collect data on targeted 
concomitant medications, SAEs, and other safety events of 
interest. The overall duration of subject participation from 
screening through follow-up is therefore approx. 13 months. 
 
Study Sites and 
Location: 
 
Subject Eligibility 
Criteria: 
Itis planned to enroll 1500 subjects (750 per antithrombotic 
regimen) in at least 150 study sites in Europe, and Asia-Pacific. 
 
OAC indication for atrial fibrillation for a period of at least 12 
months following successful PCI with stenting in adult male and 
female patients ?:18 years of age. 
 
Eligibility of pre-screened subjects is assessed 4 hours after sheath 
removal and within 5 days after successful PCI. If a staged PCI is 
planned, eligibility is assessed after completion of the last stage. 
A clinically successful PC] requires both anatomic and procedural 
success along with relief of signs and/or symptoms of myocardial 
ischemia at th-e time of randomization (for details_see Section 
4.1.l). 
 
 
 


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Subjects who·meet any of the following criteria are ineligible for 
the study: 
Bleeding risks or systemic conditions 
1. Known bleeding diathesis, including but not limited to, 
a. Uncontrolled active bleeding, encompassing both 
ISTH-major-and-clinically-relevant-non-major ----------------- ­ 
bleeding, at the time of randomization. 
b. Lesion or condition, if considered to be a significant 
risk for major bleeding. 
This may _include 
but is not limited to: unresolved 
gastrointestinal ulceration, presence of malignant 
neoplasms at high risk of bleeding (e.g. malignancies with 
l:Iletastasis), recent unresolved brain or spinal injury, recent 
brain, spinal or ophthalmic surgery, any intracranial 
hemorrhage, known or suspected esophageal varices, 
arteriovenous malformations, vascular aneurysms (of more 
than 3.5 cm) or major intraspinal or intracerebral vascular 
abnormalities. 
Medication-related 
2. INR > 2.5 (the subject can be reconsidered at a later point 
in time, but within 5 days of sheath removal). 
3. Contraindication to edoxaban, VKA, ASA and/or P2Y12 
antagonists; 
4. Concomitant treatment with other antithrombotic agents, 
fibrinolytic therapy and chronic nonsteroidal anti­ 
inflammatory drugs (NSAIDs). 
Concomitant conditions and therapies 
5. Critically ill or hemodynamically unstable subjects (at the 
time of randomization) including: 
a. cardiogenic shock or acute decompensated heart 
failure, with the requirement for vasopressor agents 
or inotropic support or mechanical support to 
support circulation 
b. respiratory failure requiring endotracheal intubation 
and mechanical ventilation. 
6. Any prior mechanjcal valvular prosthesis; 


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7. Ptanned coronary or vascular_intervention or major surgery 
within 12 months; Randomization must be deferred to the 
last stage in a multistep, multivessel PCI procedure; 
8. Moderate or severe mitral stenosis; 
9. Ischemic stroke within 2 weeks prior to randomization; 
- 
- 
-1 0. Uncontrolled-severe-hypertensionwith-a-systelic bloed ------------ ­ 
pressure (BP) 2:180 mmHg and/or diastolic BP 2:120 
mmHg; 
11. End stage renal disease (ESRD) (CrCL < 15 mL/min) or on 
dialysis; 
12. Known abnormal liver function prior to randomization 
(incl. hepatic disease or biochemical evidence of significant 
liver derangement known prior to randomization) (see 
appendix 17.4). 
Other exclusion criteria 
. 
13. Any of the following abnormal local laboratory results prior 
to randomization: 
a. Platelet count< 50 x109/L 
b. Hemoglobin < 8 g/dL 
14. Unable to provide written informed consent (IC); 
15. Female subjects of childbearing potential without using 
highly effective contraception (female of childbearing 
potential is defined as one who has not been 
postmenopausal for at least one year, or has not been 
surgically sterilised, or has not had a hysterectomy at least 
three months prior to the start o(this study).  Femal s 
taking oral contraceptives should have been on therapy for 
at least three months. Adequate contraceptives include: 
Combined (estrogen and progestogen containing) oral, 
intravaginal or transdermal hormonal contraception 
associated with inhibition of ovulation; progestogen-only 
oral, injectable or implantable hormonal contraception 
associated with inhibition of ovulation; intrauterine device 
(IUD); intrauterine hormone-releasing system (IUS); 
bilateral tubal occlusion; vasectomized partner; sexual 
abs inence 
16. Pregnant or breast-feeding subjects; 
17. Assessment that the subject is not likely to comply with the 
study procedures or have complete follow-up; 


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I8. Currently participating in another clinical trial that 
potentially interferes with the current study; 
19. Previous randomization in th_is study; 
20. Active on prescription drug abuse and addiction; abuse of 
illicit substances (i.e. marijuana, cocaine, 
  
 methamphetamine, heroin) and alcohol abuses during 
  
   
the last 12 months according to the judgement of the 
investigator 
21. Life expectancy < 12 months. 
 
 
 
Dosage Form, Dose, 
and Route of 
Administration: 
Edoxaban: 60, 30 and 15 mg provided as film coated tablets for 
oral use. 
Subjects receive 60 mg edoxaban once-daily. A dose reduction 
(30 mg edoxaban once-daily) is determined for subjects with one 
or more of the following factors: 
• 
Moderate or severe renal impairment (CrCL 15 - 50 
mL/min) 
• 
Low body weight :S 60 kg (132 lbs), 
• 
Concurrent use of P-gp inhibitors (please refer to local 
summary of product characteristics [SmPC] or to the 
Investigator Brochure [IB], as applicable); 
In EU countries, according to SmPC concomitant use of edoxaban 
with cyclosporine, dronedarone, erythromycin, or ketoconazole 
requires dose reduction to 30 mg once-daily. Concomitant use of 
edoxaban with guinidine, verapamil, or amiodarone does not 
require dose reduction. 
 
 
For low body weight (:S.60 kg) present at randomization, the 
edoxaban dose is reduced permanently a,nd even if the subject 
gains weight, the edoxaban dose remains reduced. The dose of 
edoxaban returns to the regular dosage regimen of 60 mg once­ 
daily any time the subject no longer displays any of the other 
above mentioned factors. 
After randomization and in subjects without dose reduction, if 
subject's: 
body weight drops to :S 60 kg and the body weight change 
  
is> 10% of the subject's baseline body weight, then the 
 


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edoxaban dose is reduced (i.e. to 30 mg once-daily) 
permanently. 
CrCL becomes 15 to 50 mL/min and the CrCL change is > 
20% of the subject's baseline CrCL, then the edoxaban 
dose is reduced. 
- 
 Develops the n.eed for concomitant treatment with P-gp 
inhibitors (except quinidine, verapamil or amiodarone), 
then the edoxaban dose is reduced (i.e. to 30 mg once­ 
daily). 
The dose of 15 mg edoxaban once-daily is not indicated as 
rnonotherapy and is solely provided as part of transition from 
edoxaban 30 mg at the end of study (see Section 5.3.3). 
 
 
VKA: Oral,VKA of choice, as pre-defined per country, with once- 
daily dosing for target INR between 2.0 to 3.0, inclusive. · 
VKA is supplied as commercially available tablets of the preferred 
VKA for each selected country participating in the study, being 
either: 
• 
W rfarin: 1 and 2.5 mg tablets. 
• 
Phenprocoumon: 3 mg tablets. 
• 
Fluindione: 20 mg tablets (exclusive.to France). 
• 
Acenocoumarol: 4 mg tablets. 
The Investigator monitors the INR and adjusts the VKA dose to 
maintain the INR within target. It is the Investigators 
responsibUity to collect monthly INR assessments and record 
these throughout the study. 
 
P2Y12 antagonist: 
• · Clopidogrel 75 mg, oral commercially available tablets. 
Subjects receive clopidogrel 75 mg once-daily according to the 
prescribing information, or in the presence of a documented 
clinical need (e.g. but not restricted to known dopidogrel non­ 
responder), either 
o Prasugrel 5 or 10 mg, oral commercially available 
tablets. 


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Subjects receive prasugrel 10 mg once-daily or prasugrel 5 rrig 
once-da ly if 2: 75 years of age or :S 60 kg (132 lb), according to 
the prescribing information. 
o Ticagrelor 90 mg, oral commercially available 
tablets. 
Subjects receive ticagrelor 90 mg twice-daily according to the. 
- - -p-r-es-c-ribing information. 
------------ 
 
 
A
 
lsalicylic acid (ASA): 100 mg, oral commercially available 
tablets. 
Subjects assigned to t}J.e VKA-based regimen receive 100 mg 
once-daily of ASA. In subjects assigned to the edoxaban-based 
regimen ASA is not allowed. 
Sponsor supplies participating sites with study medication, 
consisting of edoxaban, VKA (country pre-defined), P2Y12 
antagonist (clopidogrel, prasugrel or ticagrelor), and ASA. Please 
refer to the local SmPC or IB for edoxaban as applicable and to 
· the SmPC of each other study medication. 
All dosage adjustments are implemented through the IXRS. The 
IXRS provides the appropriate drug supply kit number based on 
the subject's information as provided by the Investigator. 
Study Endpoints: 
Primary endpoint: · 
The primary endpoint is the composite of major or clinically 
relevant non-major bleeding (MCRB) defined according to the 
ISTH .bleeding definitions, analyzed as time to first occurrence of 
any component. 
 
Secondary endpoints are defined as: 
Main efficacy endpoint (MEE), defined as the composite of 
· cardiovascular (CV) death, stroke, systemic embolic events 
(SEE), spontaneous myocardial infarction (MI) and definite 
stent thrombosis (as per ARC consensus definitions). 
- 
Net clinical benefit (NCB), defined as the composite of CV 
death, stroke, SEE, spontaneous MI, definite stent · 
· thrombosis and ISTH-defined major bleeding. 
- 
Main thromboembolic event, defined as composite of 
cardiac or thromboemboiic death (thromboembolic death 
considered to be thromboembolic in origin (including 
  
thromboembolic stroke, pulmonary embolism, any other 
 


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systemic embolism), ischemic stroke, SEE, spontaneous MI 
and definite stent thrombosis. 
- 
ISTH-defined major bleeding 
- 
Any bleeding defined as the composite of major, clinically 
relevant non-major and minor bleeding (ISTH definition) 
- - -- Symptomatic-intracranial-hemorrhage.OGH) -------------------------------- ­ 
Composite of stroke and SEE 
Composite of all-cause death, stroke, SEE, spontaneous MI . 
and definite stent thrombosis 
Composite of CV death, spontaneous MI and definite stent 
thrombosis· 
- 
 The single components of the composite primary and 
secondary endpoints P1entioned above are explored, as well 
as specific subcategories (e.g., hemorrhagic, ischemic and 
undetermined stroke) 
Safety parameters such as (serious) adverse events, 
laboratory parameters, ECG and vital signs. 
All secondary endpoints are analyzed as time to first occurrence of 
any of its components. 
Bleeding events are also classified according to Bleeding 
Academic Research Consortium (BARC) and Thrombolysis in 
Myocardial Infarction (TIMI) classifications for descriptive 
purposes only. All suspected bleeding events are adjudicated by 
the CEC in a blinded manner. 
All events are also sub-categorized into fatal and non-fatal. 
For all endpoints blindly adjudicated by the CEC, the CEC's 
interpretation prevails and is used in the statistical analyses. 
Planned Sample Size: The plan is to enroll 1500 subjects (750 per arm). 
Based on a review of available safety data1 the estimated one-year 
event rate of the primary endpoint (MCRB, i.e. ISTH major or 
clinically relevant non-major bleeding) under the VKA-based 
antithrombotic regimen is 24%. The edoxaban-based 
antithrombotic. regimen is anticipated to reduce the one-year 
incidence to 18% (a relative risk (RR) of 0.75). Under the 
assumption of an exponential distribution, the hazard ratio equals 
0.7231. The accrual of2 x 712 evaluable subjects provides 80% 
power to demonstrate superiority of the edoxaban-based 
  
antithrombotic regimen over the VKA-based antithrombotic 
 


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will 
 
 
regimen at a two-sided a=0.05. To compensate for censoring, the 
final sample size is set at 2 x 750 subjects. 
Statistical Analyses: Four analysis sets are defined: 
 
• 
The Intention-to-treat (ITT) analysis set consists of all 
randomized subjects iITespective whether they received a 
-   -   -  -  - ingle-dose-of-the-randomized study regimen or not-. - ------- 
•Tmodified Intention-to-treat (mITT) analysis set consists               
of all randomized subjects who received at least one dose of 
study edoxaban or study VKA according to IXRS 
assignment. 
• 
The Per Protocol (PP) analysis set consists of all 
randomiz d subjects who received at least one dose of the 
study regimen according to IXRS assignment and do not 
have any of the following major protocol violations: 
A major violation of the inclusion criteria 
- 
An unequivocal violation of the exclusion criteria, (for 
more details, see Section 11.1.3) 
• 
The Safety (SAF) analysis set consists of all randomized 
subjects who received at least one dose of the study 
edoxaban or study VKA according to IXRS assignment. 
 
Definition of terms: 
'Overall Study Period': This period is defined as the time from 
the reference date (date and time of randomization or date and 
time of first study edoxabari or study VKA intake) to Day 365. 
'OverallStudy Period+ 30 days': 
This period is defined as the 
time from the reference data (date and time of randomization or 
. date and time of first study edoxaban or study VKA intake) to 
Day 395. 
'Initial dose to Final Dose + 30 days': This period is defined as 
the-time-period between the date and time of initial dose of study 
edoxaban or study VKA and the date of final dose of study 
edoxaban or study VKA plus 30 days, including study regimen 
interruptions. 
 
The main analysis of all adjudicated primary and secondary 
exploratory endpoints 
be based on ITT analysis set and taking 
the first adjudicated event during th_e ' overall study period' into 
account. 


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For each of the primary and secondary exploratory endpoints, 
appropriate summary statistics (e.g. event rate) including 95% CI 
will be provided. 
. For each of the endpoints, the time from reference date to the first 
occurrence of an event (based on CEC adjudication), is analyzed 
using a Cox proportional hazard model with treatment regimen as 
--- 
a-factor and all-the stratification-factors-from the randomizatio,n- - 
- ­ 
(IXRS) as covariates, to provide point estimates and 95% 
Confidence Interval (Cl) for the hazard ratio (HR). Depending on 
the analysis period used in the statistical analysis, subjects without 
an occurrence of an event will be censored at the last date of the 
analysis period or at the last date of known outcomes status. The 
latter is detem1ined an individual basis for subjects with 
incomplete follow-up. 
· For time to first event analyses based on the ' overall study 
period', cumulative event rates over time are summarized using 
the Kaplan-Meier method. 
 
There are two primary hypotheses for the primary endpoint to be 
. tested in this study. 
• The edoxaban-based antithrombotic regimen is non-inferior to 
the VKA-based antithrombotic regimen with regards to MCRB. 
• The edoxaban-based antithrombotic regimen is superior to the 
VKA-based antithrombotic regimen with regards to MCRB. 
These two hypotheses are tested in a hierarchical manner, non­ 
inferiority followed by superiority to control the type-I error rate, 
with adequate power for each of the two hypotheses. 
· 
 
The primary analysis to show non-inferiority wm'be based on first 
occurrence of an (adjudicated) MCRB that occurred during the 
'overall study period' for all subjects belonging to  the ITT 
analysis set and applying the aforementioned statistical method. 
The edoxaban-based regimen will be considered non-inferior to 
the VKA-based regimen, if the upper boundary of the two-:sided 
95% CI for HR falls below 1.20. 
The primary analysis to show superiority will be based on first 
occurrence of an (adjudicated) MCRB that occurred during the 
'overall study period' for all subjects belonging to the ITT 
analysis set and applying the aforementioned statistical method. 
The edoxaban-based regimen will be compared with the VKA­ 
  
based regimen for superiority only if the non-inferiority of the 
 


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edoxaban bas_ed regimen  is established first. The edoxaban-based 
regimen will be considered superior to the VKA-based regimen, if 
the upper boun,dary of the two-si _ded 
95% CI for HR falls below 
1.00. 
To evaluate the robustness of the primary analysis, the analysis 
wiU be repeated using the mlTT and PP analysis set. In addition, 
- - --1he statistical results-based-on-the-following-analysis-perioEls ---------------------- ­ 
'initial dose to final dose+ 30 days', 'overall study period+ 30 
days' will be presented but should be interpreted in a more 
descriptive way. 
 
The main analysis for all secondary exploratory endpoints will be 
based on first occurrence of an (adjudicated) endpoint during the 
'overall s dy period' for all subjects  belonging to  the ITT 
analysis set and applying the aforementioned statistical method. 
There will be no formal statistical testing for secondary 
exploratory endpoints. HRs, CI and p-values are provided but 
should be interpreted i a purely descriptive exploratory manner. 
All details of the statistical analysis will be described in a 
statistical analysis plan (SAP). 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT .................................................................................. 2 
PROTOCOL SYNOPSIS ................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................ 17 
LIST OF IN-TEXT TABLES ......................................................................................... 24 
LIST OF IN-TEXT FIGURES ....................................................................................... 25 
LIST OF AUBREVIATIONS ......................................................................................... 26 
1. 
1.1. 
1.1.1. 
1.1.1.1. . 
1.1.1.2. 
1.1.1.3. 
1.1.1.4. 
1.1.1.5. 
1.2. 
1.2.1.1. 
1.3. 
1.4. 
1.4.1. 
1.4.2. 
1.4.3. 
2. 
2.1. 
2.1.1. 
2.1.2. 
2.1.3. 
3. 
3.1. 
4. . 
4.1. 
4.1.1. 
INTRODUCTION AND BACKGROUND INFORMATION ................ 29 
Data Summary.........··:· ...................................................................................... 30 
Investigational Product ................................................................................... 30 
Name ................................................................................:................;. .......... 30 
Description ...............,...................,......................, ......................................... 30 
Intended Use Under Investigation..............· ........................................................ 30 
Nonclinical Studies .....: ................................................................................. 30 
Clinical Experience ........................................................................................ 30 
Stu  dy.  Rat iona le   ·····:························.··················································3··2··········· 
Dose rationale ................................................................................................. 32 
Risks and Benefits for Study Subjects·....................................................; ..... 32 
Compliance Statement, Ethics and Regulatory Compliance ......................... 33 
Subject Confidentiality................................................................................... 33 
Informed Consent (IC) Procedure .................................................................. 33 
Regulatory Compliance .................................................................................. 34 
STUDY OBJECTIVES AND HYPOTHESES .......................................... 35 
Study Objectives............................................................................................. 35 
Primary Objectives.......'............................................................ 
. ..................... 35 
Secondary Exploratory Objectives ................................................................ 35 
Other Objectives ............................................................................................. 36 
STUDY DESIGN...............................................•. ............................................. 37 
Overall Plan .................................................................................................... 37 
STUDY POPULATION ............................................................................... 39 
Emollment. ..................................................................................................... 39 
Inclusion Criteria ............................................................................................ 39 


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4.1.2. 
4.2. 
4.3 
4.3.1 
4.3.2 
4.3.3 
4.4. 
4.5. 
s. 
5.1. 
5.2. 
5.2.1. 
5.2.2. 
5.3. 
5.3.1. 
5.3.2. 
5.3.3. 
5.4. 
5.4.1. 
5.4.2. 
5.4.3. 
5.4.4. 
5.5. 
5.5.1. 
5.5.2. 
5.5.3. 
5.6. 
5.6.1. 
5.6.2. 
5.7. 
5.8. 
5.9. 
Exclusion Criteria ...................................................................................... 40 
Screening failures ............................................................................................41 
Removal of Subjects from Therapy .................................................................. 42 
Reasons for Withdrawal/Early Discontinuation. ... ·.. ... . ... . ...· .......................... 42 
Withdrawal Procedure .................................................................................... 43 
Study or Site Termination .................................................................................... 43 
Subject Replacement .............._...........................................,  ............................ 44 
Subject Re-screening Procedures ................................................................... 44 
TREATMENT REGIMENS ADMINISTERED ....................................... 45 
Method of Assigning Subjects to Treatment Regimens ................................. 45 
Study  Treatment Regimens ...........................................'. ................................... 4. 5 
Edoxaban-based regimen for.12 months.........................,.............................. 45 
VKA-based regimen for 12 months (control regimen) .................................. 45 
Edoxaban ........................................................................................................ 46 
Dose ........................................................................................................... 46 · 
Transitioning to edoxaban at randomization .................................................. 47 
Transition from edoxaban at EOT .................................................................. 48 
Vitamin K Antagonist (VKA) ........................................................................ 49 
Dose .........................'..:.................................... 
.-............ 
. .... . ........ . ................... 
49 
Tra   nsitioning to Study VKA at Randomization ................................................. 50 
INR Management ........................................................................................... 50 
Transition from VKA at EQT ......................................................................... 51 
Clopidogrel (or alternative P2Y12 antagonist) ............................................... 51 
Dose ................................................................................................................ 51 
Transitioning to study P2Y12 antagonist at randomization ............................ 52 
P2Y12 inhibitor non-bleeding related adverse drug effect ............................. 52 
ASA ................................................................................................................ 52 
Dose ............................................................................:........................_  .......... 52 
Transitioning to study ASA at randomization ................................................ 53 
Interruptions and discontinuations of the assigned regimen ............................ 53 
Method of Assessing Regimen Compliance .................................................. 54 
Labeling and Packaging .........'............................. 
. ............ 
. ........ . .. . ................. 54 


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5.9.1. 
5.9.2. 
5.9.3. 
5.9.4. 
5.9.5. 
5.9.6. 
5.9.7. 
5.9.8. 
5.10. 
5.10.1. 
6. 
6.1. 
6.1.1. 
6.1.2. 
6.2. 
6.2.1. 
6.2.2. 
6.2.3. 
6.2.4.. 
6.2.5. 
6.3. 
6.3.1. 
6.4. 
6.5. 
6.5.1. 
6.6. 
7. 
7.1. 
7.2. 
7.3. 
7.3.1. 
7.3.2. 
Edoxaban ........................................................................................................ 55 
VKA ............................................................................................................... 55 
P2Y12 antagonist ............................................................................................. 55 
ASA ................................................................................................................ 56 
Preparation ...................................................................... ; ............................. 56 
Shipment receipt & Storage ........................................................................... 56 
Drug Accountability ....................................................................................... 56 
Retention Samples .......................................................................................... 57 
Prior and concomitant medications ................................................................ 57 
Prohibited Medications .................................................................................. 57 
STUDY PROCEDURES .............................................................................. 59 
Screening period (Pre-screening, Randomization/ Baseline and Discharge) 59 
Pre-screening .................................................................................................. 59 
Baseline / Randomization -  Day 1  ................................................................... 5. 9 
Treatment Period ............................................................................................ 62 
On-site Visits: 1, 3, 6, and 9 Months (±7days)or unscheduled ...................... 62 
Telephone Assessments: 2,  4, 5, 7, 8, 10 and 11 Months(± 7 days) ............. 64 
On-site Visit: 12 Months± 7 days (End-of-Treatment)................................ 65 
Additional Visits/Assessment in the VKA-based regimen ............................. 66 
Missed Follow-up Visits ................................................................................ 67 
P9st-treatment Per od·················································:······························6··7········· 
On-site Visit: 1 month post-EOT (± 7 days) .................................................. 67 
Protocol Deviations ........................................................................................ 68 
Modification ofIC after Randomization ......................................................... 68 
. 
.Subjects Lost to Follow-Up ............................................................................ 68 
End of Trial Definition ................................................................................... 69 
0 UTCOME ASSESSMENTS ..................................................................... 70 
Primary Endpoint ........................................................................................... 70 
Secondary Exploratory Endpoints .................................................................. 70 
Endpoint definitions ....................................................................................... 71 
Bleeding ......................................................................................................... 71 
Components of MEE ...................................................................................... 71 


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7.3.3. 
8. 
8.1. 
8.2. 
9. 
9.1. 
9.1.1. 
9.1.1.-1. 
9.1.1.2. 
9.1.1.3. 
9.1.1.4. 
9.2. 
9.2.1. 
9.2.2. 
9.2.3. 
9.2.4. 
9.2.5. 
9.3. 
9.3.1. 
9.3.2. 
9.4. 
9.5. 
9.5.1. 
9.5.2. 
9.6. 
9.7. 
9.8. 
9.9. 
10. 
10.1. 
10.2. 
11. 
Other ...............................................................................................................72 
PHARMACOKINETIC ASSESSMENTS ........................................................ 73 
Pharmacokinetic (PK) Variable(s) ·············:·,·····················.·.·············..···.· ..... 73 
Non-genetic biomarkers and Exploratory Variable(s) ....................................73 
SAFETY ASSESSMENTS .......................................................................... 74 
,Adverse Events (AEs) ................................................................................... 74 
Definitions ................................................................................................. 74 
Adverse Event (AE)  .......................................................................................... 7. 4 
Unexpected Adverse Event ........................................................................... 74 
Expected Adverse Event ...........................................' ................................... 74 
Serious Adverse Event (SAE) ........................................................................ 74 
Classification for AE assessment. .............................................................. 75 
Severity of Adverse Events...........................; ................................................ 75 
Relationship of Adverse Events ..................................................................... 75 
Action Taken Regarding the Assigned Antithrombotic Regimen .....................76 
Other Action Taken for Event.....,...................................................................... 76 
AE Outcome ................................................................................................... 76 
A.Es  of Special Interest ................................................................................... 77 
Combined Elevations of Aminotransferases and Bilirubin ................................ 77 
Reporting of Pregnancy/ Exposure in Utero .................................................. 77 
Timing of Adverse Event Reporting .............................................................. 78 
Reporting SAEs/AEs ...................................................................................... 78 
Documentation ............................................................................................... 78 
Notifying Regulatory Authorities, Investigators and IRB/IEC, ..................... 79 
Clinical Laboratory Evaluations .................................................................... 80 
Vi_tal Signs ...................................................................................................... 81 
Electrocardiograms .............................................................................................. 81 
Physical Findings ........................................................................................... 81 
OTHER ASSESSMENTS............................................................................ 82 
Coronary angiograms ..................................................................................... 82 
Hospitalisations .............................................................................................. 82 
STATISTICAL METHODS ................................;......_  ................................. 83 


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11.1. 
11.1.1. 
11.1.2. 
11.1.3. 
11.1.4. 
11.2. 
11.3. 
11.4. 
11.4.1. 
11.4.1.1. 
11.4.1.2. 
11.4.2. 
11.43. 
11.4.3.1. 
11.4.3.2. 
11.4.3.3. 
11.4.3.4. 
11.4.4. 
11.5. 
ll.5.1. 
11.5.2. 
11.5.3. 
11.5.4. 
11.5.5. 
11.6. 
11.7. 
11.8. 
11.9. 
12. 
12.1. 
12.2.. 
12.3. 
 
Analysis Sets .................................................................................................. 8.3. 
Intention-to-treat analysis set ..................................................................... 83 
Modified Intention-to-treat analysis set .......................................................... 83 
Per Protocol analysis set ................................................................................. 83 
Safety analysis set ........................................................................................... 84 
General Statistical Considerations ................................................................. 84 
Study Population Data.................................................................................... 85 
Statistical Analysis ......................................................................................... 86 
Analysis of the primary endpoint..................................:··..··· .......................... 86 
Test for non-inferiority .............................................................................. 86 
Test for superiority ..................................................................................., .... 87 
Analysis of the secondary exploratory endpoints .......................................... 87 
Pharmacokinetic/Pharmacodynamic Analysis ................................................. 87- 
Pharmacokinetic Analyses ............................................................................. 87 
Pharmacodynamic Analyses ................·..........................................· .................. 87 
Biomarker Analyses........................................................_.  ................................ 87 
Pharmacogenomic Analyses ......................................................................... 87 
Health Economics Outcome Research (HEOR) Analyses ............................. 88· 
Safety Analyses...........................................................................................8  8 
Adverse Event Analyses ........·.........................'................................................... 88 
Clinical Laboratory Evaluation Analyses ...................................................... 88 
Vital Sign Analyses ........................................................................................ 88 
Electrocardiogram Analyses........................................................................... 89 
Physical Examination Analyses ..................................................................... 89 
Other Analyses ............................................................................................... 89 
Interim Analyses ............................................................................................. 89 
Data and Safety Monitoring Board (DSMB) .................................................. 89 
Sample Size Determination ............................................................................ 89 
DATA INTEGRITY AND QUALITY ASSURANCE .............................. 91 
Monitoring and Inspections ............................................................................ 91 
Data Collection ............................................................................................... 91 
Supply of New InformationAffecting the Conduct of the Study ................... 91 


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12.4. 
12.5. 
12.6. 
13. 
13.1. 
. 13.2. 
14. 
15. 
15.1. 
15.2. 
15.2.1. 
15.2.1.1. 
15.2.1.2. 
15.2.2. 
15.2.3. 
15.2.3.1. 
15.2.3.2. 
15.2.4. 
15.2.4.1. 
15.2.4.2. 
15.2.5. 
15.2.6. 
16. 
17. 
17.1. 
17.1.1. 
17.1.2. 
17.1.3. 
17.1.4. 
17.1.5. 
17.2. 
17.3. 
Data Management ........................................................................................... 92 
Study Documentation and Storage ................................................................ 92 
Record Keeping ............................................................................................. 93 
FINANCING AND INSURANCE·······'.···················· 
· ················ · ................... 94 
Finances ......................................................................................................... 94 
Reimbursement, Indemnity, and Insurance.................................................... 94 
PUBLICATION POLICY ........................................................................... 95 
STUDY ADMINISTRATIVE INFORMATION ....................................... 96 
Protocol Amendments .................................................................................... 96 
Address List ................................................................................................... 96 
Sponsor ........................................................................................................... 96 
DSE Project Leader ........................................................................................ 96 
DSE Medical Expert ...................................................................................... 96 
Academic Research Organizations ····:···············································9·6····· 
CRO .......................................................................................................... 97 
CRO Medical Monitor .................................................................................... 97 
CRO Project Manager ..............: ..................................................................... 97 
Drug Safety ..................................................................................................... 97 
DSE ........................................................................................................... 97 
CRO .........................· .............................................................................................. 97 
Interactive Web Voice Response System (IXRS) .......................................... 97 
Bioanalytical Laboratory .......; ........................................................................... 98 
REFERENCES ..................................................................................................... 99 
APPENDICES ............................................................................................. 103 · 
Study Organizati9n ....................................................................................... 103 
Data and Safety Monitoring Board (DSMB) ................................................ 103 
Clinical Events Committee (CEC)..............., ................................................ 103 
Executive Committee............................................................................, . 104 
Steering Committee ....................................................................................... 104 
Operations Committee .................................................................................. 104 
Substudies ................................................: ................................................... 104 
ISTH Bleeding Criteria ................................................................................. 105 


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.17.4. 
Definition of terms ............................................................................................ 106 
17.5. 
Components of the CHA2DS2-VASc Score and HAS-BLED Score ........... 107 
17.6. 
. Estimation of Creatinine Clearance (CrCL) ................................................... 09 
17.7. 
Modified Rankin Scale ................................................................................. 110 
17.8. 
Regional Guideline Recommendations for INR .......................................... 110 
17.9. 
Schedule of Events .................................................................................. 111 


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Protocol DSE-EDO-0 1715-EU 
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LIST OF IN-TEXT TABLES 
Table I.I: 
Table 5.2: 
Table 5.3: 
. 
 Table 5.4: 
Table 5.5: 
Table17.l: 
Table 17.2: 
Table 17.3: 
Table 17.4: 
Table 17.5: 
Table 17.6: 
Summary of the Hokusai VTE and ENGAGE AF-TIMI 48 Studies ......... 32 
Transitioning to edoxaban at randomization ............................................. 46 
Transitioning from Edoxaban at EOT ....................................................... 47 
Transitioning to Study VKA at Randomization ........................................ 49 
Transitioning to Study VKA at EOT. ........................................................ 50 
ISTH Bleeding Criteria ································:······'·················· .......................... 101 
Components of the CHA2DS2-VASc Score ........................................... 103 
Components of the HAS-BLED Score .................................................... 104 
Modified Rankin Scale.........."...................................... 
. ........................... 
106 
Regional Guideline Recommendations for INR ...................................... 106 
Schedule of Events .................................................................................. 107 


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LIST OF IN-TEXT FIGURES 
'Figure 3.1 Study Design .................................................................................................... 38 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
ACS 
Acute Coronary Syndrome 
AE 
Adverse Event 
AESf 
Advei·se Event of Special Interest 
AF 
Atrial Fibrillation 
ALP 
-- 
- 
- - 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ARC 
Academic Research Consorti um 
ARO 
Academic Rese;a,c h Organization 
AST 
Aspartate Transaminase 
ASA 
Acetylsalicylic Acid 
BARC 
Bleeding Academic Research Consortium 
BP 
Bloo d Pressure 
BUN 
Blood Urea Nitr gen 
CAD 
Coronary Artery Disease 
CABG 
Coronaty Atiery Bypass Graft 
CrCL 
Creatinine Clearance 
CEC 
Clinical Events Committee 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
CKMB 
Creatine Kinase MB Isoform 
CRNM 
Clinically R levant Non-Major 
' 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
cTn 
Cardiac Troponin 
CV 
Cardiovascular 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMA 
European Medical Agency 
EOT 
End-of-Treatment 
EIU 
Exposure In Utero 
EudraCT 
European Union Drug Regulati ng Authorities Clinical Trials 
FXa 
Factor Xa 
GCP 
Good Clinical Practice (refers to ICH) 
GI 
Gastrointestinal 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HR 
Hazard Ratio 
1B 
Investigator Brochure 


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ABBREVIATION 
DEFINITION 
IC 
Informed Consent 
!CF 
Informed Consent Form 
ICH 
Interi1ational Conference on Harmonization 
1D 
Identiftcation 
IEC 
Independent Ethics Committee 
-INR 
International-Norma lized-Ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Hemostasis 
ITT 
Intent-To-Treat 
IXRS 
Interactive Web/Voice Response System 
LLT 
Lower Level Term 
MCRB 
Major or Clinically Relevant Non-major Bleeding 
MEE 
Main Efficacy Endpoint 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
mITT 
Modified ITT 
NCB 
Net Clinical Benefit 
NOAC 
Non-vitamin K Antagonist Oral Anticoagulant 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NVAF 
Non-Valvular Atrial Fibrillation 
OAC 
Oral Anticoagulant 
P-gp 
P-Glycoprotein 
PCI 
Percutaneous Coronary Intervention 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
pp 
Per Protocol 
PROBE design 
Prospective, Randomized, Open-label study with Blinded Evaluation of endpoints 
pSOC 
Primary System Organ Class 
SAE 
Serious Adverse Event 
SAF 
Safety. 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SEE 
Systemic Embolic Events 
SAVER 
Serious Adverse Event Report 
SOP 
Standard Operating Procedures 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction 
TBL 
Total Bilirubin 
TIA 
Transient Ischemic Attack 
ULN 
Upper Limit of Normal 
VKA 
Vitamin K Antagonist 


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ABBREVIATION 
DEFINITION 
Vs 
Versus 
VTE 
Venous Thromboembolic Event 
WBC 
White Blood Cells 
 
 
 


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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
Up to one-third of patients with atrial fibrillation (AF) have concomitant coronary artery disease 
(CAD) and may require stent placement to treat symptomatic stable CAD or acute coronary 
syndromes (ACS).(2) The optimal antithrombotic treatment for patients with AF following 
coronary stenting has not be n well established. (1, 3) 
Dual antiplatelet therapy with aspirin and P2Y12 antagonist is cmTently recommended after PCI 
with stent placement.(4, 5) 
Chronic oral anticoagulation is recommended in patients with AF at moderate or high risk of 
thromboembolism.(6, 7) Non-vitamin K antagonist oral anticoagulants (NOACs) are an 
alternative to Vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular AF 
(NVAF). (3) 
Therapy with an oral anticoagulant (OAC), aspirin, and clopidogrel (P2Y12 inhibitor) is 
generally considered the standard of care for patien-ts with AF following coronary stent 
placement.(1, 3, 4) Consensus recommendations (1, 8-10) have endorsed the use of such therapy 
with the duration of treatment with the individual drngs being guided by type of stent, bleeding 
risk, and clinical presentation (i.e., stable coronary disease or acute coronary syndrome 
(ACS]).(1, 7-11) However, therapy with OAC, aspirin and clopidogrel is associated with 3- to 
4-fold increased risk of bleeding complications. 
The 2014 AHA/ACC/HRS AF guidelines (11) state that "following coronary revascularization 
(percutaneous or surgical) in patients with AF.and a CHA2DS2-VASc score of2 or greater, it 
may be reasonable to use clopidogrel (75 mg once-daily) concurrently with O C but without 
aspirin." This recommendation is class Ilb, such that it "may/might be considered," 
"usefulness/effectiveness is unknown/unclear/uncertainor not well established," and "additional 
studies with broad objectives needed." The "level of evidence B" is based on the WOEST trial 
(12), a relatively small exploratory study in which therapy with V,{(A plus clopidogr l was 
associated with a significant reduction in bleeding complications and fewer thrombotic events 
compared with therapy with VKA, aspirin, and clopidogrel. 
Edoxaban is a factor X;:i inhibitor (NOAC); tested in the ENGAGE AF-TIMi 48 trial.(13) 
Edoxaban was non-inferior to warfarin (VKA) with respect to the prevention of stroke or 
systemic embolism and was associated with significantly lower _rates 
of bleeding and death from 
cardiovascular causes in patients with non-valvular AF.(13) 
· 
There are insufficieI_lt data on the safety and efficacy of edoxaban plus antiplatelet therapy in 
subjects with AF following PCI with stenting. This study is designed to evaluate the safety and 
to explore the efficacy of an edoxaban-based antithrombotic regimen versus a VKA-based 
antithrombotic regimen in subjects with AF following PCI with stent placement. Bleeding is a 
central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies 
and invasive procedures (14-16). 


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1.1. 
Data-Summary 
 
1.1.1. 
Investigational Product 
 
1.1.1.1. 
Name 
Name oflnvestigational Product: Edoxaban tosylate (DU-l 76b). 
Edoxaban (InternationaJ-n on -::proprietary 
- na me)-;-an hydrousfree-base-(DU-176). 
 
1.1.1.2. 
. Description 
Edoxaban tosylate is an antithrombotic agent, an or lly active, selective, direct, and reversible 
inhibitor of Factor Xa (FXa), manufactured by Daiichi Sankyo Co., Ltd., Japan. Inhibition of 
FXa in the coagulation cascade prolongs clotting time and potentially reduces the risk of 
spontaneous or induced thrombus formation. 
Edoxaban refers to the anhydrous free base of edoxaban tosylate. Subjects are given edoxaban 
tosylate (a monohydrate salt) but all doses and plasma concentrations are expressed in terms of 
edoxaban, the anhydrous free base. 
For simplicity, this protocol uses the term "edoxaban" to refer to either or both forms. 
 
1.1.1.3. 
Intended Use Under Investigation 
The proposed indication is to use edoxaban in subjects with AF following successful PCI with 
stent placement. 
 
1.1.1.4. 
Nonclinical Studies · 
In nonclinical studies, edoxaban showed excellent potential as an antithrombotic agent. Results 
of non-clinical toxicology studies do not indicate ariy major clinically concerning adverse effects 
in study animals exposed to edoxaban. ·Additional details are available in the edoxaban 
Investigators' Brochure (17). 
 
1.1.1.5. 
Clinical Experience 
Edoxaban has been approved and is marketed in Japan for the indication of prevention of 
ischemic stroke and systemic embolism in patients with non-valvular AF; treatment and 
recurrence prevention of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary 
thromboembolism); and prevention ofvenous thromboembolism in patients undergoing any of 
the following rthopedic procedures on the lower limb: total knee replacement, total hip 
replacement, and hip fracture surgery. 
The efficacy and safety of edoxaban for reducing the risk of stroke and SEE in subjects with 
non-valvular AF ha-s been demonstrated in a large pivotal Phase 3 study (ENGAGE AF-TIMI 
48) (13). 
Similarly, the efficacy and safety of edoxaban for the treatment of VTE, including deep vein 
thrombosis and pulmonary embolism, and the prevention of recurrent VTE has been 
demonstrated in a Phase 3-Hokusai VTE study(18). 
Features of the Hokusai VTE and ENGAGE AF-TIMI 48 studie.s are summarized in Table.1.1. 


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Table 1.1: Summary of the Hokusai VTE and ENGAGE AF-TIMI 48 Studies 
Study 
Population 
Median 
Duration 
of 
Treatment 
Treatment Groups N 
Primary Efficacy Outcome 
Primary Safety Outcome 
Endpoint 
HR (95% Cl) 
Edoxaban vs 
Warfarin 
Endpoint 
HR (95% Cl) 
Edoxaban vs 
Warfarin 
Hokusai 
VTE (acute 
VTE) 
Edoxaban_60 mg 
Warfarin 
,U !8 
4122 
0.89 (0.103,-1.128)_ 
mIIT , overall study 
period 
Major-+- 
CRNM _ 
Bleeding 
0.8 1-(0.705 , 0.936 ) 
mIIT , on-treatment 
period 
0.7 years 
"Recur rent 
VTE 
ENGAGE 
AF-TIMI 
48 (NVAF) 
2.5 years 
Edoxaban 
High Dose 
Regimen* 
7035 
Stroke 
and SEE 
0.79 (0.63, 0.99) 
mITT, on-treatment 
period 
Major 
Bleeding 
0.80 (0.71, 0.91) 
mITT, on-treatment 
period 
Edoxaban 
Low Dose 
Regimen** 
7034 
1.07 (0.87, 1.3I) 
mIIT, on-treatment 
period 
0.47 (0.41, 0.55) 
m!IT on-treatment 
period 
Warfarin 
7036 
. 
- 
Abbreviations: CI = confidence interval; CRNM = clinically relevant non-major; HR = Hazard Ratio; 
NVAF = nonvalvular atrial fibrillation; SEE= systemic embolic event; vs= versus; VTE = venous 
thromboembolism; mlTT = modified intention-to-treat; N = number of subjects 
*High Dose Regimen= 60mg edoxaban once-daily with reduction to 30mg once-dafly in patients with low body 
weight, moderate renal impairment, or specified concomitant medications; 
**Low Dose Regimen= 30mg edoxaban once-daily with reduction to I5mgonce-daily in patients with low body 
weight, moderate renal impairment, or specified concomitant medications. 
 
 
Other completed studies include Phase I clinical pharmacology studies, Phase 2 dose-ranging 
studies in subjects with NYAF'and subjects undergoing lower-extremity orthqpedic surgery, and 
Phase 3 studies in subjects undergoing lower-extremity orthopedic surgery. 
In the course of the edoxaban clinical development program, oyer 23,500 subjects have been 
given edoxaban encompassing over 34,100 subject-years of exposure. 
 
 
The safety and efficacy bf edoxaban has been evaluated in the following programs: 
• 
Phase I studies (including 1627 subjects from pharmacokinetic (PK)-pharmacodynamic 
(PD) studies, PK in subjects with renal impairment, and drug-drug interaction studies): 
Results of these studies have shown that edoxaban is rapidly absorbed with rapid onset of 
action and the dose concentration relationship is generally linear. The mean terminal half­ 
life ranges between 5 and 11 hours. The pharmacodynamic effect as measured by anti-Xa 
activity or inhibition of factor Xa activity lasts for 24 hours. Dose-related increases in PK 
concentrations and anti-thrombotic activity were observed, as measured by anti-Xa 
activity. The bioavailability is ~60% and 50% of the absorbed drug is excreted by renal 
clearance. The absorption, distribution, metabolism, and excretion are also mediated 
through the P glycoprotein (P-gp) transport system and drugs with P-gp inhibitory effects 
may alter edoxaban exposure. 
• 
Phase 2 studies in AF subjects (including 1,952 subjects): These studies primarily 
evaluated safety of different dose regimens of edoxaban with approximately 12 weeks of 
treatment. Results of these studies showed that the twice a day (BID) regimen had higher 


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bleeding than once-daily regimen of edoxaban. Consequently, the once-daily regimen ·of 
edoxaban was tested in the subsequent Phase 3 trials. · 
• 
Phase 3 pivotal trial (ENGAGE AF-TIMI 48(13)) involving 21,105 subjects with a 
median follow-up of 2.8 years. Two once-daily regimens of edoxaban were compared 
with warfarin for the prevention of stroke and systemic embolism in patients with non­ 
valvular atrial fibrillation. Both regimens were non-inferior to warfarin for the prevention 
ef--stroke -a nd-systemic-embolism-and-w re-associated-with-significantly-lower rates o 
bleeding and death from cardiovascular causes. Edoxaban has been approved for 
marketing in US and in Europe for this indication. 
• 
Phase 2/3 VTE prophylaxis studies in subjects undergoing orthopedic surgery (including 
3,678 subjects). Edoxaban.has been approved for marketing in Japan f<:>r this indication. 
• 
Phase 3 pivotal trial (Hokusai-VTB (18)) involving 8,292 randomized subjects. Edoxaban 
administered once-daily after initial treatment with heparin was non-inferior to standard 
· therapy and caused significantly less bleeding in patients with VTE. 
 
1.2. 
Study Rationale 
Up to one-third of patients with AF have concomitant coronary artery disease and may require 
stent placement to treat symptomatic stable coronary artery disease or acute coronary 
syndromes. The optimal antithrombotic treatment for patients with AF following coronary 
stenting has not been well established. 
This study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based 
antithrombotic regimen versus a VKA-based antithrombotic regimen in subjects with AF 
following PCI with stent placement. 
1.2.1.1. 
Dose rationale 
Bc:tsed on the results of the ENGAGE AF-TIMI 48(13) and Hokusai(l8) studies, an edoxaban 
dose that i_s consider_ed as safe and effective for patients with AF or venous thromboembolism 
and is included in the label (prescribing information) has been selected for this trial. Edoxaban 
has not been evaluated in patients with AF undergoing PCI with stent placement but no 
additional evidence exists suggesting further dose adaptation. 
 
 
1.3. 
Risks and Benefits for Study Subjects 
Subjects with AF undergoing PCI with stent placement require the use of OACs with single or 
dual antiplatelet therapy (i.e., a P2Y12 antagonist and acetylsalicylic acid such as aspirin) to 
reduce the risk of stroke, SEE, stent thrombosis and other myocardial ischemic events, and 
related cardiovascular morbidity and mortality. While the concomitant use of OACs with· 
antiplatelet agents reduces the risk of thromboembolic events, such therapy also increases the 
risk of bleeding events. Furthermore, the combination of a P2Y12 antagonist with aspirin given 
without OACs is less effective than OACs alone in preventing stroke and SEE in patients with 
AF(19). 


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1.4. 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Council for 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); 
• 
European Data Protection Directive 95/46/EC; 
• 
Other applicable local regulations. 
 
 
1.4.1. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in ccordance with GCP, the rules laid down for the protection of individuals with 
regard to the processing of personal data and the free movement of such data and other local 
regulations. 
For• European Union (EU) study centers, the Sponsor will observe the rules laid down in the 
European Data Protection Directive 95/46/EC on the protection of individuals with regard to the 
processing of personal data and the free movement of such data. 
The Investigator must ensure that the subject's anonymity is maintained. On the Case Report 
Forms (CRFs) or other documents submitted to the Sponsor, subjects should be identified by a 
unique subject identification number as designated by the sponsor. The Investigator.must 
obliterate any private information contained on documents (e.g. name or address) prior to 
passing them oil to the sponsor or CRO. Documents that are not for submission to either 
Sponsor or CRO (e.g., signed Informed Consent [IC]) should be kept in strict confidence by the 
Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
Independent Ethics Committee (IEC) direct access to review the subject's original medical 
records for _verification of study-related procedures and data. 
 
1.4.2. 
Informed Consent (IC) Procedure 
Before a subject's participation in the study, it is the Investigator's responsibiJity·to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any study drugs are administered. Subjects must have the opportunity 
to ask questions and receive satisfactory answers to their inquiries, and must have adequate time 
to decide whether or not to participate in the study. The written ipformed consent form (ICF) is 
prepared in the local language(s) of the potential subject population. 


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1.4.3.. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator's Brochure, any 
subject diary card or written instructions to be given to the subject, available safety information, 
subject recruitment procedures, information about payments and compensation available to the 
subjects and documentation evidencing the Investigator's qualifications should be submitted to 
the IEC for ethical review and approval according to local regulations, prior to the study start. 
- - - +he-written-approval-should identify all doeuments-reviewed-by-name-and-versio,n-. ------ 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment arid/or the Statistical Analysis Plan (SAP). 
All subsequent substantial protocol amendments and changes to the IC document will be 
submitted to the IEC for approval. The Investigator should notify the IEC of deviations from the 
protocol or serious adverse events occurring at the site and other adverse event reports received 
from Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor's local Regulatory Affairs group or delegate will 
insure 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 is to compare a  12-month  antithrombotic regimen  of  edoxaban  in 
combination with clopidQgr  Lor_anot her E2Y-12 antagonist again'sca reg 
imen_o f_a YK 
A  , in  .  
 
_ 
combination with clopidogrel or  another  P2Y12 antagonist and  t  least  I-month ASA  in  subjects 
with AF following successful PCI with stent placement in  terms of  the incidence of  major or 
clinically relevant non-major ISTH-defined bleeding (MCRB). 
There are two primary hypotheses for bleeding to be tested in this study. 
• 
The edoxaban-based antithrombotic regimen is non-inferior to the VKA-based 
antithrombotic regimen with regards to MCRB. 
• 
The edoxaban-based antithrombotic regimen is superior to the VKA-based antithrombotic 
regimen with regards to MCRB. 
These two hypotheses are tested in a hierarchical manner, non-inferiority followed by superiority 
to control the type-I error rate, with adequate power for each of the two hypotheses. 
 
 
2.1.2. 
Secondary Exploratory Objectives 
Secondary exploratory objectives of the study are to compare the edoxaban-based antithrombotic 
regimen to the VKA-based antithrombotic regimen with regard to: 
• 
Main efficacy endpoint (MEE), defined as the composite of cardiovascular (CV) death, 
stroke, systemic embolic events (SEE), myocardial infarction (MI) and definite stent 
thrombosis. 
• · Net clinical benefit (NCB), defined as the composite of CV death, stroke, SEE, MI, 
.definite stent thrombosis and ISTH-defined major bleeding. 
• 
Main thromboembolic event, defined as composite of cardiac or thromboembolic death 
(thromboembolic death considered to be thromboembolic in origin (including 
thromboembolic stroke, pulmonary embolism, any other systemic embolism), ischemic 
stroke, SEE, MI and definite stent thrombosis. 
• 
ISTH-defined major bleeding 
• 
Any bleeding defined as the composite of major, clinically relevant non-major, and minor 
bleeding (ISTH definition) 
• 
Symptomatic intracranial hemorrhage (ICH) 
• 
Composite of stroke and S E 
• 
Composite of all-cause death, stroke, SEE, MI and definite stent thrombosis 
• 
Composite of CV death, MI and definite stent thrombosis 


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• 
The single components of the composite primary and secondary endpoints mentioned 
above are explored 
• 
Safety parameters such as (serious) adverse events, laboratory parameters, ECG and vital 
signs_. 
 
 
- 
- 
2 --:-1:J. 
Otfier Ooject1ves 
Not applicable. 


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3. 
STUDY DESIGN 
 
3.1. 
Overall Plan 
This is a multinational, multicenter, randomized, open-label Phase 3b study with blinded 
evaluation of endpoints by an independent CEC (PROBE design). At least 150 sites will be 
required to enroll 1500 subjects (750 subjects per antithrombotic regimen) in Europe, and Asia- 
   Paci,fic -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   -   - 
 
 
A schematic presentation of the study design is provided in Figure 3.1. 
The study is divided into a screening period (incl. pre-screening), a treatment period and an 
observational post-treatment follow-up period. The screening period starts after a percutaneous 
coronary intervention (PCI) with stent placement. Subjects with an OAC indication for AF for at 
least 12 months who have successfully undergone a PCI and who received a stent are eligible for 
inclusion in the study. 
Subjects should satisfy the pre-screening criteria before IC is signed. Once written, IC is 
obtained, and eligibility criteria (inclusion and exclusion) are met subjects are randomized 
without delay (1:1 ratio), to one of two treatment groups being an edoxaban-based regimen 
(index regimen) and a VKA-based regimen (control regimen). Consenting and randomization 
takes place within 4 hours and 5 days post-PCI and before hospital discharge. If a staged PCI is 
planned, consenting and randomization takes place after successful completion of the last stage. 
The edoxaban-based regimen consists of treatment with edoxaban 60 mg once-daily and 
clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 or 
10 mg once-daily] /or ticagrelor [90 mg twice-daily]) for 12 months. 
The VKA-based regimen, dosed to achieve a target INR of2.0- 3.0, in combination with 
clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 or 
10 mg once-daily] /or ticagrelor (90 mg twice-daily]) for 12 months and ASA (100 mg once­ 
daily) for 1-12 months. These regimens are detailed in Section 5. The assigned regimen is 
. implemented·after'randomization without any due delay (please refer to Section 5). The 
randomized regimens (edoxaban-based or VKA-based) and clopidogrel (or other P2Y12 
antagonist) are continued for 12 months, when the scheduled end-of-treatment (EOT) is reached. 
Subject clinical visits are planned at 1, 3, 6, 9 and 12 months after randomization. All subjects 
have telephone assessments at 2, 4, 5, 7, 8, 10 and 11 months after randomization. All 
information must be captured in the eCRF and study assessments are performed according to the 
visit schedule provided under appendix Section 17.9. All subjects are followed for 12 months 
irrespective of changes in the antithrombotic regimen. Clinical follow-up is only terminated at 
the explicit request of the subject. All subjects on either edoxaban or VKA at 12 months, have a 
contact planned 1 month after the end-of-treatment visit, to collect data on targeted concomitant 
medications, SAEs, and other events of interest. The overall duration of subject participation 
from scre ning through follow-up is therefore approx. 13 months. 
The study organization, including the CEC, DSMB, Executive Committee and Steering 
Committee are described in appendix section 17.1. Ai:i independent DSMB reviews pertinent 
study data to protect the safety of the subjects participating in the study. 
 
 
 
/ 


 
d of treatment (EO 
Vi:sit   2 months 
diathesis 
' , 
' '""==========  ====  ====== ======  ====== =========►
=    -----..,..,.... 
P2Y12 antagonist** 
(ASA 1 - 12 months)**** 
Vitamin K antagonist (VKA) *** 
4h - 5d 
,, 
Prima
outcome: 
I 
Protoco DSE-EDO-01-15-EU 
Version .0, 28 February 20.17 
 
 
 
 
 
 
 
 
Edoxaban 
60 
En                    
mg once-daily• 
T)  Fiinal follow-up 
Vil 
30d post-EQT 
 
Inclusion criteria: 
• OAC indication for 
AF for at least 12 
"'•t."
•I!WI  / 
 
  a I 
P2Y12   antagonist** 
I 
(without A' A) 
 
 
 
Ke excl. criteria: 
• Known bleeding 
after 
' , 
sheath- 
'\ 
removal 
' ,,, 
 
 
 
 
 
 
 
• Edoxaban dose reduction to 30 mg once-daily if either CrCL s 50 mUmin, or body weight s 60 kg, or concomitant therapy with certain 
P-gp inhibitors. •• Clopidogrel 75mg once-daily (or in the presence of a documented clinical need prasugrel [5 or 10 mg once daily] / 
ticagrelor [90 mg twice daily] may be used).••• VKA of choice with dosing for target international normalized ratio (INR) of.2 0 
- 3.0 inclusive ........ ASA (100 mg once-daily) for 1-12 months guided by the clinical presentation (ACS or stable coronary I isease), 
and upon the CHA2DSr   VASc and HAS-BLED score. 
§ Goal of at least 25% ACS. 
AF, atrial fibrillation: ACS, acute coronary syndrome: PCI, percutaneous coronary intervention; ISTH, International Society on 
Thrombosis and Haemostasis; CRNM, clinically relevant non-major; h, hours: d, days. 
 
 
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Figure 3.1 Study Design 
ENTRUST AF-PCI Study 
• 
stent placement§ 
Successful PCI with
months 
CRNM-bleeding 
ISTH major &


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4. 
STUDY POPULATION 
 
4.1. 
·Enrollment 
Investigators maintain a confidential pre-screening log of all potential study 
candidates (i.e. subjects with an OAC indication for AF for at least 12 months who 
-   - --nave  -s uccessfully-undergone-a-PG!) that-includes limited information-of th,{'>--------------------- ­ 
subjects (age, sex), date and outcome of screening process (e.g:, enroll in the 
study, reason for refusal to participate). _ 
Investigators will be expected to maintain an Enrollment Log of all subjects 
enrolled in the study indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list. This 
confidential list of names of all subjects allocated to study numbers on enrolling in 
the study, allows the Investigator to reveal the identity of any subject when 
necessary. 
A subject is considered to be enrolled after the subject has provided written IC. An 
unique study identification number is provided through the IXRS together with the 
randomized treatment assignment. 
 
 
4.1.1. 
Inclusion Criteria 
OAC indication for atrial fibrillation for a period of at least 12 months following 
successful PCI with stenting in adult male and female patients 2:18 years of age. 
Eligibility is assessed 4 hours after sheath removal and within 5 days after 
successful PCI with stent placement. If a staged PCI is planned, eligibility is 
assessed after completion of the last stage. 
 
Successful PCI definition: 
The success of a PCI procedure is defined by 2 interrelated components: 
angiographic findings, procedural / clinical outcomes as detailed below: 
a) Angiographic Success 
A minimum stenosis diameter of< 20% (as visually assessed by angiography - 
residual blockage or stenosis reduced to less than 20% of the artery's diameter). 
Sufficient enlargement of the lumen at the target site to improve coronary artery 
blood flow with final TIMI flow grade 3 (visually assessed by angiography), 
withou·t occlusion of a significant side branch, flow-limiting dissection, distal 
embolization, or angiographic thrombus. 
b) Procedural Success 
No major in-hospital clinical complications (e.g. ongoing ISTH qiajor or 
clinical relevant non-major procedural bleeding at the time of randomization, 
stroke, emergency CABG). 


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In summary, a clinically successful PCI requires both anatomic and procedural 
success along with relief of signs and/or symptoms of myocardial ischemia at the 
time of randomization. 
 
 
4.1.2. · 
Exclusion Criteria 
Subjects who meet any of the following critena are disqualified from entering the 
study: 
Bleeding risks or systemic conditions 
1. Known bleeding diathesis, including but not limited to, 
a. Uncontrolled active bleeding, encompassing both ISTH major and 
clinically relevant non-major bleeding, preceding randomization. 
b. Lesion or condition, if considered to be a significant risk for major 
bleeding. 
This may include but is not limited to: unresolved gastrointestinal ulceration, 
presence of malignant neoplasms at high risk of bleeding (e.g. malignancies with 
metastasis), recent unresolved brain or spinal injury, recent brain; spinal or 
ophthalmic surgery, any intracranial hemorrhage, known or suspected esophageal 
varices, arteriovenous malformations, vascular aneurysms (of more than 3.5 cm) 
or major intraspinal or intracerebral vascular abnormalities. 
Medication-related 
2. INR > 2.5 (the subject can be reconsidered at a later time, but within 5 days· 
of sheath removal). 
3. Contraindication to edoxaban, VKA, ASA and/or P2Y12 antagonists; 
4. Concomitant treatment with other antithrombotic agents, fibrinolytic 
therapy n4 chronic nonsteroidal anti-inflammatory drugs (NSAIDs). 
Concomitant copditions and therapies 
5. Critically ill or hemodynamically unstable subjects (at the time of 
randomization) including: 
a. cardiogenic shock or acute decompensated heart failure, with the 
requirement for vasopressor agents or inotropic support or 
mechanical support to support circulation 
b. respiratory failure requiring endotracheal intubation and mechanical 
ventilation. 
6. Ariy prior mechanical valvular prosthesis; 
7. Planned coronary or vascular intervention or major surgery within 12 
months; Randomization must be deferred to the last stage in a multistep, 
multivessel PCI procedure; 
8. Moderate or severe mitral stenosis; 
9. Ischemic stroke within 2 weeks prior to randomization; 


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10. Uncontrolled severe hypertension with a systolic blood pressure (BP) 2.180 
mmHg and/or diastolic BP 2. 120 mmHg; 
11. End stage renal disease (ESRD) (CrCL < 15 mL/min) or on dialysis; 
12. Known abnormal liver function prior to randomization (incl. hepatic disease 
or biochemical evidence of significant liver derangement known prior to 
randomization) (see appendix 17.4). 
 
 
Other exclusion criteria 
13. Any of the following abnormal local laboratory results prior to 
randomization: 
a. Platelet count < 50 x109/L 
b. Hemoglobin < 8 g/dL. 
14. Unable to provide written TC; 
15. Female subjects of childbearing potential without using highly effective 
contraception (female of childbearing potential is defined as one who has 
not been postmenopausal for at least one year, or has not been surgically 
sterilised, or has not had a hysterectomy at least three months prior to the 
start of this study). Females taking oral contraceptives should have been on 
therapy for at least three months. Adequate contraceptives include: 
Combined (estrogen and progestogen containing) oral, intravaginal or 
transdermal hormonal contraception associated with inhibition of ovulation;. 
progestogen-onlyoral, injectable or implantable hormonal contraception 
associated with inhibition of ovulation; intrauterine device (IUD); 
intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; 
vasectomized partner; sexual abstinence 
16. Pregnant or breast-feeding subjects; 
17. Assessment that the subject is not likely to comply with the study 
procedures or have complete follow-up; 
18. Participating in another clinical trial that potentially interferes with the 
current study; 
· 
19. Previous randomization in this study; 
20. Active on prescription drug abuse and addiction; abuse of illicit substances 
(i.e. marijuana; cocaine, methamphetamine heroin) and alcohol abuses 
during the last 12 months according to the judgement of the investigator 
21. Life expectancy < 12 months. 
 
 
4.2. 
Screening failures 
 
 
Subjects are pre-screened based on the information available from the standard 
care. For subjects fulfilling the pre-screening (i.e., OAC indication for AF for a 
period of at least 12 months and successful PCI with stenting), IC signature and 
other study-specificscreening procedures take· place just prior to randomization. A 


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subject who withdraws IC before randomization or who fails the 
inclusion/exclusion criteria before randomization is defined as a screening failure. 
No further clinical follow-up is performed for these subjects. 
 
 
4.3. 
Removal'of Subjects From Therapy 
 
4.3.1. 
Reasons for Withdrawal/Early Discontinuation 
The subject is free to withdraw from the study for any reason and at any time 
without giving reason for doing so and without penalty or prejudice. The 
Investigator is also free to terminate a subject's involvement-in the study at any 
time if the subject's clinical condition warrants it. It is also possible that the · 
sponsor or the competent authorities request termination of the study if there are 
concerns about conduct or safety. 
Participation of a subject in this clinical study should be discontinued at all periods 
(except where noted) for any of the following reasons: 
1. Withdrawal of Subjects consent at any time of the study 
2. Occurrence of any medical condition or circumstance that exposes the 
subject to substantial risk (including inter alia, stent thrombosis and major 
haemorrhage) and/or does not allow the subject to adhere to the 
requirements of the protocol. 
3. Any SAE, clinically significant AE, severe laboratory abnormality, 
intercurrent illness, other medical condition, or change in the subject's 
condition which indicates to the Investigator that continued participation is 
not in the best interest of the subject for any reason, including ethics. 
4. Females who become pregnant at any time during the study period must be 
discontinued immediately and counselled appropriately. The Investigator 
must follow the pregnancy to completion of term. 
5. Requirement of prohibited concomitant medication. 
6. Subject failure to comply with protpcol requirements or study related 
procedures. 
7. Termination of the study by the Sponsor or regulatory authorities. 
8. When patients reach a primary endpoint or key safety endpoint (including 
but not limited to definite acute stent thrombosis, disabling stroke (modified 
Rankin score 2 at 90 days plus increase in 1 mRS category from the pre­ 
stroke baseline)), the investigator needs to decide if study medication will 
be permanently discontinued, interrupted, modified or continued. In case of 
intracranial bleeding the protocol mandates stopping the study treatment. 
 
 
 
If a subject 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 last study medication dose and the reason for withdrawal. 


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If the subject is withdrawn due to an AE (including clinically relevant laboratory 
abnormalities); the Investigator will follow the subject until the AE has resolved, 
stabilised, or can be explained by reasons not attributable to the investigational 
product. 
All subjects who are withdrawn from the study should complete protocol specified 
withdrawal procedures (Section 6.2.3 end of study). 
 
4.3.2. Withdrawal procedures 
If the Investigator removes a subject from the study or if the subject withdraws 
consent for any reason.after receiving the first dose, a complete set of Early 
Withdrawal visit should be carried out, preferably prior to the subject being placed 
on alternative therapy. 
An Early Withdrawal Visit will include the same assessments and procedures as 
the end-of-treatment visit (section 6.2.3). Additionally, the date study medication 
was last taken will be recorded. The Investigator should start the subject on 
appropriate oral anticoagulant treatment (see section 5.3.) and the prescription 
should be recorded in the eCRF, if the information is available. 
All results of evaluations and observations, pertinent to the study, together with a 
description ofreason(s) for withdrawal must be recorded in the eCRF. If a subject . 
is withdrawn from the study due to an AE, the event must be recorded on the AE 
page of the eCRF. Any additional study-specific procedures conducted due to the 
AE should be recorded on the eCRF as an unscheduled procedure. Any subject 
with an SAE or an AE that led to study medication discontinuation will be 
followed until the subject returns to baseline conditions or stabilises. 
 
 
4.3.3. Study or ite terminations 
If the Sponsor or their representatives, Investigator, or CA officials discover 
conditions during the study that indicate that the study or site involvement should 
be terminated. Conditions that may warrant termination of the study or 
involvement of a study site include, but are not limited to: 
• 
The discovery of an unexpected,.serious, or unacceptable risk to patients 
enroll.ed in the study. 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, 
evaluatiqn, or development of the study drug. 
• 
Failure of the Investigator(s) to comply with pertinent clinical trial 
regulations. 
• 
Submission of knowingly false information from the research facility to the 
Sponsor, Clinical Monitor, or the Clinical Research Assistant. 
• 
Insufficient adherence to protocol requirements 
• 
Study termination and follow-up will be performed in accordance with 
applicable local regulations." 


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4.4 Subject Replacement 
Not applicable. 
 
 
4.5 Subject Re-screening Procedures 
If during study_ ualification: 
  
 
• a staged PCI is planned, eligibility is assessed after completion of the last 
stage of PCI 
· 


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5. 
TREATMENT REGIMENS ADMINISTERED 
 
5.i. 
Method of Assigning Subjects to-Treatment Regimens 
After the IC has been signed and eligibility confirmed, the Investigator contacts 
the IXRS to assign an individual study identification number. 
The Investigator should be prepared to provide subject information, including, but 
nor--limited-to-:age-;-bodr weight;-clinical presentation-[ACS-ot stab1e," c=o=r=on=a=r=y.  ---------------------- ­ 
artery disease (CAD)], CrCL using Cockcroft-Gault formula (see Section 17.6) 
and whether the subject is taking concomitant P-gp inhibitors requiring edoxaban 
dose reduction (according to local SmPC or 1B as applicable). 
Randomization is stratified by clinical presentation (ACS or stable coronary 
disease), requirement for dose adjustment of edoxaban, and by geographical 
region (i.e. Latin America, Western Europe, Eastern Europe, Asia, as applicable). 
Subjects will be assigned randomly via the above mentioned IXRS such that the 
study has a I:1 ratio of subjects in the two antithrombotic treatment regimens. 
The specifications for generation of the randomization schedule will be prepared 
by the study biostatistician and the IXRS vendor. An independent biostatistician, · 
not otherwise part of the study team, will generate the randomization schedule. 
For this study, the randomization sched. ule refers to a list that includes the subject 
identification number (ID), randomization block' number, and randomization 
treatment. 
 
 
5.2. 
Study Treatment Regimens 
 
5.2.1. 
Edoxaban-based regimen for 12 months 
• 
Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects (see 
Section 5.3.1). 
• · Clopidogrel 75 mg once-daily (or in the presence of a documented clinical 
need prasugrel [5mg or 10 mg_ once-daily]or ticagrelor [90 mg twice-daily] 
may be used). 
• 
The use of a P2Y12 antagonist other than clopidogrel must be pre-declared. 
• 
Concomitant use bf another anti-platelet agent (i.e. ASA) is not allowed. 
 
 
5.2.2. 
VKA-based regimen for 12 months (control regimen) 
• 
Oral VKA of choice with dosing for target international normalized ratio 
(INR) between 2.0 - 3.0, inclusive. 
• 
Clopidogrel 75mg once-daily (or in the presence of a documented clinical 
need prasugrel [10 mg once-daily]/ ticagrelor [90 mg twice-daily] m_ay 
be 
used). 
• 
ASA (100 mg once-daily) for a minimum of 1 month and up to 12 months 
duration at the Investigator discretion guided by the clinical presentation 


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(ACS or stable CAD), and upon the CHA2DS2-VASc and HAS-BLED 
score (1). 
• 
The useof a P2Y12 antagonist other than clopidogrel must be pre-declared, 
together with the intended duration of ASA treatment. 
 
For simplicity, this protocol uses the term "edoxaban" to refer to edoxaban tosylate, 
"clopidogrel" to refer to clopidogrel bisulfate and the term....'.!pras    ugrel" to refer to prasugref-   ­ 
hydrochloride. 
Pre-declaration means that the Investigator specifies this info1mation in the IXRS, prior to 
randomization and assignment to an antithrombotic regimen. 
 
 
 
3. 
Edoxa ban 
Edoxaban tosylate (DU-l 76b, trade names Lixiana®, Savaysa®), referred 
throughout this protocol by the term "ed9xaban" for simplicity, is part of the 
edoxaban-based regimen. Please refer to Section 5.9 Labeling and Packaging. 
According to local SmPC or 1B as applicable, subjects may take edoxaban with or 
without food, in the morning or evening, but at approximately the same time every 
day. 
If a dose of edoxaban is missed, the dose must be taken as soon as possible as long 
as on the same day. The dose of edoxaban must not be doubled to make up for a 
missed dose. 
 
 
5.3.1. 
Dose 
Edoxaban 60 mg once-daily. 
At randomization, the recommended dose of edoxaban is 30 mg once-daily in 
subjects with 1 or more of the following factors: 
• . Moderate or severe renal impairment (calculated CrCL 15 - 50 
mL/min), 
• 
Low body weight of 
60 kg (132 lbs), 
• 
Concurrent use of P-gp inhibitors (please refer to local SmPC or to 
IB, as applicable). 
In EU countries, according to SmPC concomitant use of edoxaban 
with cyclosporine, dronedarone, erythromycin, or ketoconazole 
requires dose reduction to 30 mg once-daily. Concomitant use of 
edoxaban with quinidine, verapamil. or amiodarone does not 
require dose reduction. 
 
All edoxaban dosage adjustments will be implemented through the IXRS. The 
IXRS will provide the appropriate drug supply kit number. 


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J::or low body weight (::S 60 kg) present at randomization, the edoxaban dose is 
reduced permanently and even if the subject gains weight,.the edoxaban dose 
remains reduced. 
The dose of edoxaban returns to the regular dosage regimen of 60 mg once-daily 
any time the subject no longer displays any of the other above mentioned factors. 
After randomization and in subjects without dose reduction, if subject's: 
body weight drops to ::S 60 kg and the body weight change is > 10% of the 
subject's baseline body weight, then the edoxaban dose is reduced  (i.e.,  to 
30 mg once-daily) permanently. 
CrCL becomes 15 to 50 mL/min and the CrCL change is> 20% of the 
subject' s baseline CrCL, then the edoxaban dose is reduced. 
Develops the need for concomitant treatment with certain P-gp inhibitors 
which require edoxaban dose adjustment, then the edoxaban dose is reduced 
(i.e., to 30 mg once-daily). 
The dose of 15 mg edoxaban once-daily is not indicated as monotherapy and is 
solely provided as part of transition from edoxaban 30 mg at the end of study (see 
Section 5.3.3). 
 
 
5.3.2. 
Transitioning to edoxaba,n at randomization 
For subjects randomized to the edoxaban-based regimen that require switching 
from another anticoagulant the following algorithm should be used. Capture the 
date and timing of first study dose in eCRF. 
 
Table 5.2: Transitioning to edoxaban at randomization 
 
Switching to edoxaban 
From 
To 
Recommendation 
VKA 
edoxaban Discontinue the VKA and start edoxaban when INR is :S 2.5 . 
Other non-VKA OAC 
drugs 
• dabigatran 
• rivaroxaban 
• apixaban 
edoxaban Discontinue the OAC and start edoxaban at the time of the 
next OAC dose. 
Parenteral anticoagulants 
edoxaban 
These agents should not be administered simultaneously. . 
Subcutaneous anticoag_ulant (i.e. LMWH, fondaparinux): 
discontinue subcutaneous anticoagulant and start edoxaban at 
the time of the next scheduled subcutaneous anticoagulant 
dose. 
Intravenous unfractionated heparin: 
Discontinue the infusio·n and start edoxaban 4 hours later. 


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5.3.3. 
Transition from edoxaban at EOT 
For subjects randomized to the edoxaban.,.based reg imen that require switching 
from edoxaban to another anticoagulant at the scheduled EOT (or due a premature 
edoxaban discontinuation) th following algorithm should be used. 
 
 
 
T- a"-ble 5.3.· Transitioning_from_Edoxaban-at.EQT 
Switching from edoxaban 
From 
To 
Recommendation 
- 
edoxaban 
VKA 
During the transition from edoxaban to VKA continuous adequate 
anticoagulation should be ensured during any transition to an alternate 
anticoagulant. 
Oral option: 
• 
For subjects currently on a 60 mg once-daily dose, administer 
an edoxaban dose of 30 mg once-daily together with an 
appropriate VKA dose. 
• 
For subjects currently on a 30 mg dose once-daily (for one or 
more of the following factors: moderate to severe renal 
impairment (CrCL I5 - 50 mt/min), low body weight, or use 
with certain P-gp inhibitors), administer an edoxaban dose of 
15 mg once-daily together with an appropriate VKA dose. 
Edoxaban 15 mg once-daily is not indicated as monotherapy, 
as it may result in decreased efficacy. It is only indicated in 
the process of switchi·ng from edoxaban 30 mg once-daily to 
VKA, together with an appropriate VKA dose. 
Subjects should not take a loading dose ofVKA in order to promptly 
achieve a stable INRbetween 2.0 and 3.0. It is recommended to take 
into account the maintenance dose ofVKA if the patient was 
previously taking a VKA or to use valid INR driven VKA treatment 
algorithm, in accordance with local practice. 
Once an INR 2.0 is achieved, edoxaban should be discontinued. Most 
patients (85%) should be able to achieve an INR   2.0  within 14 days 
of concomitant administration of edoxaban and VKA. After 14 days it 
is recommended that edoxaban is discontinued and the VKA continued 
to be titrated to achieve an INR between 2.0 and 3.0. It  is 
recommended that during the first 14 days of concomitant therapy the 
INR is measured at least 3 times just prior to taking the daily dose of 
edoxaban to minimize the influence of edoxaban on INR 
measurements. Concomitant edoxaban and VKA can increase the INR 
post edoxaban dose by up to 46%. 
Parenteral option: 
Discontinue edoxaban and administer a parenteral anticoagulant and 
VKA at tn.e time of the next scheduled edoxaban dose. Once a stable 
INR of 
2.0 is achieved, the parenteral anticoagulant should be 
discontinued and the VKA continued. 
edoxaban 
Other non- 
VKAOAC 
drugs 
Discontinue edoxaban and start the non-VKA anticoagulant at the time 
of the next scheduled dose of edoxaban. 


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Switching from edoxaban 
From 
To 
Recommendation 
edoxaban 
Parenteral 
anticoagulant 
s 
These agents should not be administered simultaneously. Discontinue 
edoxaban and start the parenteral anticoagulant at the time of the next 
scheduled dose of edoxaban. 
 
 
5.4. 
Vitamin K Antagonist (VKA) 
An approved/marketed VKA will be supplied as the preferred VKA for each 
selected country participating in the study. All VKA dispensations must take place 
through the IXRS that will provide the appropriate drug supply kit number. 
In addition, the Investigator monitors the INR and adjusts the VKA dose to 
maintain the target INR between 2.0-3.0 inclusive. It is the Investigators 
responsibility to collect monthly INR assessments and record these throughout the 
study. 
 
 
5.4.1. 
Dose 
· A preferred vitamin K antagonist (VKA) is selected for each participating country 
which is provided as study medication: - 
Warfarin 
Loading dose from 2 to 5 mg once-daily for 2-4 days followed by a maintenance 
dose of 2 to 10 mg once-daily adjusted by INR values to maintain target INR 
between 2.0 -3.0 inclusive. 
Phenprocoumon 
Weekly dose calculation ofup to 9 mg on day 1, 6 mg on d y 2 and maintenance 
doses between 1.5 to 6.0 mg once-daily thereafter, adjusted by INR values to 
maintain target INR between 2.0 -3.0 inclusive. 
Fluindione 
The initial daily dose of 20 mg is adjusted by INR values to maintain target INR 
between 2.0 -3.0 inclusive. In subjects at particular risk of bleeding (weight <50 
kg, elderly, hepatic impairment), the initial dose is usually lower. No loading dose 
should be used. 
The dose adjustment is performed in accordance to the package insert and usually 
by increments of 5 mg (1/4 tablet). 
Acenocoumarol 
The usual starting dose in a normal weight person is between 2 mg/day to 4 
mg/day without administration of a loading dose, if the INR value before the start 
of treatment is within the normal range. Trel:ltment may also be initiated with a 
loading dose regimen, usually 6 mg on the first day followed by 4 mg on the 


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second day. The maintenance dose generally lies between 1 and 8 mg once-daily, 
aµjusted by INR values to maintain target INR between 2.0 -3.0 inclusive. 
The dosing of the aforementioned VK.As must be individualized. The maintenance 
dose varies from subject to subject and its appropriateness must b checked 
individually on basis of INR values. 
The Investigator or designee is responsible for dispensing the VKA antagonist and 
- 
 m=u=s  ensure tfiat drug supplieffoy Sponsor is used in accordance with, 
and the VKA package insert. 
th--e=--pro- tocol-- - - - - - - - - 
 
 
5.4.2. 
Transitioning to Study VKA at Randomization 
For subj cts randomized  to VKA who require switching from another 
anticoagulant (another VKA, other non-VKA OAC drugs or parenteral 
anticoagulants,), follow the guidance for switching in the locally approved labels of 
these products. Capture the date and timing of first study dose in eCRF. 
 
Tal:ile 5.4: Transitioning to Study VKA at Randomization 
 
Switching to VKA 
From 
To . 
Recommendation 
 
 
Vitamin K Antagonist 
(VKA) 
Study VKA 
If the INR measured on the day ofrandomization 
is: 
• 
:52.5, start study VKA 
• 
> 2.5, the Investigator or designee must 
recheck at a later time; start study VKA 
when the INR is :52.5: document the 
INR value and the date it was measured. 
Other non-VKA OAC 
drugs 
• 
dabigatran 
• 
rivaroxaban . 
• 
apixaban 
StudyVKA 
Ascertain adequate anticoagulation until an INR 
2'.2.0 is reached and then continue with study 
VKA only. Follow local label of country-selected 
VKA and label ofNOAC being stopped for 
further guidance. 
 
Parenteral 
anticoagulants 
Study VKA 
For subjects not previously on VKA, bridging 
with parenteral anticoagu _lation is permissible, but 
not recommended. For initiation ofVKA therapy 
and related bridging with parenteral 
anticoagulation, follow locally 'established 
guidelines and local approved label (prescribing 
information) from the VKA manufacturer. 
 
 
5.4.3. 
INR Management 
Every effmt should be made to optimize the VKA dosing and INR monitoring 
schedule to maintain INR values between 2.0-3.0 inclusive. 
INR management is according to the standard of care and may be performed by 
the Investigator, the subject's primary care physician or other private physician, at 


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a specialized anticoagulation clinic or patient self-monitoring. Close attention to 
the INR management plan and frequent monitoring of INR values is strongly 
recommended to optimize the VKA treatment and maintain the subject's INR 
values between 2.0-3.0 inclusive. The Investigator will ensure the VKA is used 
according to the approved label (prescribing information). 
Daily INR determinations upon initiation should be obtained until subject's INR is 
stable in the therapeutic range. It may take 4-14 days to attain the target - ­ 
therapeutic range of INR 2'.. 2.0. 
Obtain subsequent INR determinations as per recommendations and guidelines 
provided in the local approved label from the respective VKA manufacturer. 
 
 
5.4.4. 
Transition from VKA at EOT 
 
Table 5.5: Transitioning to Study VKA at EOT 
 
Switching from VKA 
From 
To 
Recommendation 
Study VKA 
VKA 
When transitioning a subject to post-study VKA, 
eit he·r maintain the subject on the same 
maintenance dose or adjust the dose ofVKA to 
maintain an TNR between 2.0-3.0 and follow the 
local guidelines for managing patients on VKA 
therapy. 
Study VKA 
Other non-VKA OAC 
drugs 
When transitioning a subject to a newer non-VKA 
oral anticoagulant,switching guidance in the 
locally approved label of the non-VKA 
anticoagulant should be followed. 
 
 
S.S. 
Clopidogrel (or alternative P2Y12 antagonist) 
The P2Y12 antagonist clopidogrel is part of both the edoxaban-based and the 
VKA-based regimen. Please refer to Section 5.9 Labeling and Packaging. 
 
5.5.1. 
Dose 
Clopidogrel bisulfate 75mg once-daily as provided by sponsor. 
In the presence of a documented clinical need (e.g. known hypersensitivity to 
clopidogrel or its_excipients, known CYP2C19 poor metabolizer-clopidogrel 
non-responder, among others ) the use of a P2Y12 antagonist other than 
clopidogrel is allowed but must be pre-declared prior to randomization. 
Either prasugrel [5 or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be 
used according to the regional clinical practice guidelines for the dose and 
administration of the respective P2Y12 antagonist. The Investigator should follow 
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the relevant SmPC and the applicable regional guidelines regarding dose and 
transition from or to another P2Y12 antagonist. 
The 5 mg once-daily dose of prasugr l should be give n as maintenance dose in 
subjects with body weight< 60 kg. The use of prasugrel in subjects 
75 years of 
age is generally not recommended but if treatment is deemed necessary, then a 
reduced maintenance dose of 5 mg once-daily should be prescribed in subjects in 
this age group. For additional details please consult the SmPC and the drug-­ 
package insert. 
Both prasugrel 5 or 10 mg once-daily and ticagrelor 90 mg twice-daily will be 
provided by the sponsor and dispensed through the IXRS. The Investigator or 
designee is responsible for dispensing the P2Y12 antagonist through the IXRS and 
must ensure that drug supplied by sponsor is used only in accordance with the 
protocol and to the drug package insert. 
 
 
5.5.2. 
Transitioning to study P2Y12 antagonist at randomization 
For subjects randomized to either the edoxaban-based or the VKA-based regimen 
discontinue the P2Y12 antagonist being taken and start study clopidogrel (or . 
alternative study P2Y12 antagonist) at the time of the next dose. Capture the date 
and timing of first study dose in eCRF. 
 
5.5.3. 
P2Y12 inhibitor non-bleeding related adverse drug effect 
Subjects must follow the P2Y12 antagonist pre-declared prior to randomization for 
12 months. In the presence of a documented P2Y12 antagonist drug specific side 
effect excluding bleeding, cross-over to another study P2Y12 inhibitor .is allowed. 
A P2Y12 inhibitor of similar potency is recommended wherever possible and if the 
treating physician considers it safe and the clinical situation allows doing so. 
E.g.: subject on ticagrelor as pre-declared prior to randomization develops 
dyspnea as drug-specific side effect - cross-over to another P2Y12 is a llowed and 
prasugrel is recommended. 
 
 
5.6. 
ASA 
ASA is only part of the VKA-based regimen. Please refer to Section 5.9 Labeling 
and Packaging. 
 
5.6.1. 
Dose 
ASA 100 mg once-daily as provided by sponsor.is administered in the VKA-based 
regimen for a minimumof 1 month and up to 12 months. In case the ASA dose 
before randomization was other than 100 mg once-daily, the dose has to be 
adjusted to 100 mg once-daily immediately after randomization. The duration of 
the ASA treatme nt in the VKA-based regimen is pre-declared by the Investigator 
prior to randomization guided by the clinical presentation (ACS or stable coronary 
disease), and upon the CHA2DS2-VASc and HAS-BLED score. The Investigator 
follows the applicable regional clinical guidelines (1). 


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The Investigator or designee is responsible for dispensing ASA through the IXRS 
and must ensure that drug supplied by sponsor is used only in accordance with the 
protocol and to the drug package insert. 
ASA is prohibited in the edoxaban-based regimen throughout the 12 months of 
planned treatment. 
· 
 
       ,5.6.2     
 Tr,,ans      itioning-to study-ASA-at-fandomization  ---------------------------------------------------- ­ 
For subjects randomized to the VKA-based regimen only discontinue ASA as 
being taken and start study ASA at the time of the next dose. Capture the date and 
timing of first study dose in eCRF. 
 
 
· 5.7. 
Interruptions and discontinuations of the assigned regimen 
The intended duration of the two treatment regimens is 12 months (i.e., 365 days). 
Subjects stay on the assigned OAC-based regi en as much as possible. 
Permanent discontinuation of the assigned regimen is mandatory if the.CrCL falls 
below 15 mL/min on two consecutive occasions or if subject is placed on dialysis. 
If the Investigator doubts the accuracy of the CrCL value calculated with the 
Cockcroft-Gault formula, he/she may consider calculating CrCL using a 24 hour 
urine collection, for confirmatory purposes. If a subject's CrCL, calculated with 
either the Cockcroft-Gault formula or 24 hour urine collection, recovers to > 15 
mL/min, the subject should resume study regimen in line with the applicable 
labels. 
· 
For subjects with a suspected transient decrease in CrCL < 15 mL/min it is 
recommended that repeat testing of CrCL occur after corrective action is taken or 
when the medical condition that caused the worsening renal function resolves. The 
timing of the repeat testing is at the discretion of the Investigator and will vary 
depending on the nature of the medical condition (e.g., 1-2 weeks for urinary tract 
infection or overdiuresis vs. several weeks to months for glomerulonephritis). 
 
If other clinical contraindications for any study medication develop (according to 
the label of the respective drug), the study medication must be discontinued (or 
dosedecreased if applicable). If the contraindication resolves, the respective study 
medication is restarted. During each interruption of anticoagulant or antiplatelet 
therapy, subjects are evaluated to determine whether the subject can safely resume 
the study drug. A post-randomization change in health status that results in the 
subject meeting one or more of the exclusion criteria should only lead to 
interruption or discontinuation of the assigned medications if the change in health 
status implies a contraindication according to the drug labels. 
Study medications are permanently discontinued if th·e subject refuses 
continuation of any medication in the assigned study regimens. If refusal of the 
subject is restricted to a single study drug, this drug is discontinued while the other 
drugs are continued unchanged. 
· 


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All subjects are followed for 12 months irrespective of changes in the 
antithrombotic regimen. Clinical follow-up is only terminated at the explicit 
documented request of the subject (see Section 6.5). 
All study medication start and stop dates are captured in eCRF together with the 
reason for interruption or discontinuation. 
 
 
5.8. 
Method of Assessing Regimen Compliance 
The first dose of each of the randomized study medication regimen is administered 
under nursing supervision. Each subject receives a medication log at each visit 
where missed doses should be captured and Investigator captures information in 
theeCRF. 
At each visit, the Investigator or designee assesses the subject's compliance with 
the a signed regimen by asking the subject about missed doses and visually 
inspecting the drug supply the subject brought to the visit. The Investigator or 
designee assesses the compliance of edoxaban, P2Y12 antagonist and ASA by 
tablet counts, and captures information in the eCRF. If zero tablets are returned 
while an overage is expected, the subject should be asked whether any were 
disposed/thrown away, rather than taken orally. 
 
 
Moreover, the Investigator captures the exposure to edoxaban, VKA, P2Y12 
antagonist and ASA in the eCRF: 
The information provided by the subject on their medication log. 
Information provided by subject during site visits or site telephone assessments 
concerning missed doses (date, drug and reason). 
For VKA, the Investigator assesses the INR at local lab at each on site visit and 
uses the determined INR value in the assessment ofVKA exposure and target 
INR between 2.0-3.0. In addition, the Investigator will contact the subject by 
telephone each month (if no visit is scheduled) and record INR valu.es in 
between site visits. It is the Investigators responsibility to: 
o  monitor the INR and adjust the VKA dose to maintain the INR within 
target 
o collect monthly INR assessments and record these throughout the study. 
In case of a suspected study endpoint, an additional assessment for subject . 
compliance to the assigned regimen must be performed. 
 
 
5.9. 
Labeling and Packaging 
The Investigators/study coordinators must ensure that the appropriate fields on the 
label are completed, including unique subject identification (ID). 
The Investigator provides the subjects with sufficient study medications to last 
unti"l the next scheduled dispensing visit. 


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For each study medication, a reserve kit is provided at the first study regimen 
dispensation. The subject is instructed to use each medication pack completely 
.  before staiting a new pack. The reserve kit of each medication should only be used 
in case the s bject is out of study medication before reaching his/her next 
scheduled visit. If the reserve kit is needed, it must be used completely before 
starting a new pack. In this case the last kit of the next dispensation is changed to 
  
"reserve kit". 
 
  
 
  
 
 
 
5.9.1. 
Edoxaban 
Edoxaban is supplied as 15, 30 or 60 mg tablets in monthly wallets with blisters 
and will be provided to all sites. Materials are supplied in their original primary 
packaging and labelled with a single panel multilingual booklet. 
 
 
5.9.2. 
VKA 
Materials are supplied in their original primary packaging and labelled with a 
single panel multilingual booklet. Sponsor provides an oral preferred VKA as pre­ 
selected by country, being either: 
Warfarin supplied as commercially available tablets of 1 mg, and 2.5 mg in 
monthly wallets with biisters. 
Phenprocoumon supplied as commercially available tablets of 3 mg strength in 
monthly wallets with blisters. 
Fluindione supplied as commercially available tablets of 20 mg strength in 
monthly wallets with blisters. Fluindione suppl·y is exclusive to France and will 
not be available in other participating countries. Fluindione is only labelled in 
French. 
- 
Acenocoumarol supplied as commercially available tablets of 4 mg strength in 
monthly wallets with blisters. 
 
 
5.9.3. 
P2Y12 antagonist 
Sponsor provides the P2Y12 antagonists which is packaged in monthly wallets 
with blisters. Materials are supplied in their original primary packaging and 
labelled with a single panel multilingual booklet. 
Clopidogrel will be supplied as commercially available 75 mg film-coated tablets. 
In addition, prasugrel and ticagrelor will also be provided for subjects with a 
documented clinical need and as pre-declared at randomization. Prasugrel will be 
supplied as commercially available 5 mg film-coated tablets. Ticagrelor will be 
supplied as commercially available 90 mg film-coated tablets. 


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5.9.4. 
ASA 
Sponsor provides ASA whichis supplied as commercially available 100 mg 
tablets packaged in monthly wallets with blisters (primary package). Secondary 
protocol-specific packaging and labeling will be completed by an approved 
packaging and labeling facility according to GMP and national requirements. 
 
5.9.5. 
Preparation 
All investigational products will be supplied as tablets that need no further 
preparation at the sites. 
 
5.9.6. 
Shipment receipt & Storage 
When a drug shipment is received, the Investigator or designee will do the 
following within 48 hours of receipt: check the amount and condition of the drug, 
check for appropriate local language on the label, check the drug expiration date, 
and sign the Receipt of Shipment Form provided. The site will acknowledge 
receipt of the shipment in the IXRS. All instructions on the Receipt of Shipment 
Form will be followed, and the form will be filled in at the site. In addition, the 
Investigator or designee will contact the site monitor as soon as possible but 
within 48 hours, if there is a problem with the shipment. 
Drug supplies must be stored in a secure, limited access storage area under the 
recommended storage conditions as measured by a minimum/maximum 
thermometer. Temperature measurement will be recorded daily on a temperature 
log, excluding weekends and holidays. The sponsor and site monitor must be 
contacted in the event of a temperature excursion outside of the recommended 
storage conditions. 
 
 
5.9.7. 
Drug Accountability 
The eCRF contains a drug accountability module for any medications supplied by 
the sponsor. The Investigator or designee enters the required information in this 
module. 
At the end of the study, or as .directed, all medications supplied by the sponsor, 
including unused, partially used, or empty containers, will be returned to a 
designee as instructed by DSE. Investigational Product will be returned only after 
the study monitor has completed a final inventory to verify the quantity to be 
returned. The return of all study medications must be documented and the 
documentation included in the shipment. At the erid of the study, a final study 
medication 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 DSE and DSE has received copies of 
. the site's drug handling and disposition SOPs. 
All inventory forms must be made available for audits by a sponsor authorized 
representative or designee and /or inspections by regulatory agency inspectors. 
The Investigator is responsible for the accountability of all used and unused 
medications provided by the sponsor at the site. 


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. 
 
 
 
5.9.8. 
Retention Samples 
It is not be necessary to store retention samples of drugs at the study sites. 
 
5.10. 
Prior and concomitant medications 
Prior medications that the subject has taken within 30 days before randomization 
are recorded in the eCRF. These medications taken by the subjects prior to 
ranaomization or at any time during the studyare regarded as concomita 
 
medications and must be documented on the appropriate pages of the eCRF. 
If the subject experiences a study endpoint event (see Section 7.land 7.2, 
including individual components) or an SAE, then information on concomitant 
medications taken within the past 30 days must be documented in the appropriate 
eCRF pages. 
Concomitant medication use is captured inthe eCRF until the post-EOT visit. 
 
 
Gastric protection agents are encouraged, as in guideline and consensus 
statements, especially for patients deemed to be at risk for gastrointestinal 
bleeding (20). The use of esomeprazole is recommended as it can be administered 
in combination with edoxaban without dose adjustment. 
 
 
Medications listed below are allowed with the following restrictions: 
• 
In the VKA-based regimen, study ASA is allowed if dose 
100 mg 
once-daily 
• 
In the edoxaban-based regimen, edoxabari dose reduction to 30 mg 
once-daily is required during concomitant use with certain P-gp 
inhibitors(please refer to local SmPC or to the IB, as applicable); In EU 
countries, according to SrnPC concomitant use of edoxaban with. 
cyclosporine, dronedarone, erythromycin, or ketoconazole requires dose 
requction to 30 mg once-daily. Concomitant use of edoxaban with 
quinidine. verapamil. or amiodarone does not require dose reduction. 
 
 
5.10.1. 
Prohibited Medications 
The following drug·s are not permitt d during the treatment period: 
• 
Anticoagulants, other than the assigned edoxaban or VKA, by any route 
(with the exception of parenteral agents used to treat a new clinical 
event, such as acute coronary syndrome, or as a bridge when starting or 
resuming the assigned edoxaban or VKA); 
• 
In the edoxaban-based regimen, concomitant treatment with ASA; 
• 
Fibrinolytic agents, unless required to treat a new clinical event, such as 
acute MI, PE, or stroke, in which case the risks and benefits of such 
treatment should be considered and, if given, the assigned edoxaban or 
VKA should be temporarily discontinued; 


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• 
Chronic use (i.e., for 2:: 4 days/week) of oral or parenteral non-steroidal 
anti-inflammatory drugs (NSAIDs) including both cyclooxygenase-1 
(COX-I) and cyclooxygenase-2 (COX-2) in. hibitors.  Study ASA is 
permitted as pre-defined for the VK.A-based regimen only. Use of 
NSAIDs via other routes (e.g., topical, inhaled, intranasal, intraocular, 
etc.) is not restricted; 
• 
lnvestigationalarugs (otfier tfian tfie randozyuzed study treatment 
regimen). 
 
 
Subjects on these drugs at the time of randomization are excluded from the study. 
After randomization, concomitant use of these drugs will require a study 
medication interruption. All study medication interruptions must be captured in the 
eCRF. After completion of the course of therapy with the prohibited concomitant 
drug, the interrupted study medication should be resumed. 


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6. 
STUDY PROCEDURES 
The study is divided into a screening period, a treatment period and an 
observational post-treatmentfollow-up period. Subjects with an OAC indication 
for AF for at least 12 months who have·undergoneeither elective or urgent PCI 
with stent placement successfully, are evaluated for potential participation in this 
study (included in pre-screening). 
· 
A tabular summary of the visit schedule for the study is provided in Appendix 
17.9. All medications used in the study regimens are provided by the Sponsor and 
details on drug accountability are provided in Section 5.9.7. 
 
 
6.l. 
Screening period (Pre-screening, Randomization / Baseline and 
Discharge) 
Subjects will undergo study procedures only after the IC is signed and IC may 
only be obtained after the successful PCI procedure, when subject is considered 
eligible and when randomization is envisioned. Subjects who meet all inclusion 
criteria and none of the exclusion criteria may be randomized (Section 4.1.1and 
4.1.2). 
It is anticipated that most subjects have the described pre-screening procedures as 
part of standard of care outside the auspices of this study. Any protocol-specified 
study screening procedures/tests which are not part of standard of care need to be 
conducted after the subject signs the IC and before randomization. 
6.1.1. 
Pre-screening 
The following activities and/or assessments are performed at/during study 
screening: 
• 
A re-check that the subject meets all of the inclusion criteria and 
none of the exclusion criteria (see Section 4.1); 
• 
Last local laboratory test results, done post-index PCI: 
- Estimated CrCL (according to the Cockcroft-Gaultformula, see 
Appendix 17.6), 
Hemoglobin (Hgb), 
- platelet count, and 
- WBC (with differential if elevated.). 
• 
Checking the last available INR value (pre-:-randomization), done 
within the past 24 hours; INR must be :S 2.5 
 
 
6.1.2. 
Baseline/ Randomization - Day 1 
Prior to randomization: 
• 
After contacting the IXRS, the Investigator provides the following 
information to the IXRS: 


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- 
Confirm tion written IC has been obtained; 
- 
Confirmation subject fulfills all inclusion and none of the 
exclusion criteria; 
Demography (age, body weight and gender); 
Clinical presentation (ACS or stable CAD); 
 
 
- 
Last value of estimated Creatinine clearance (CrCL); 
- 
INR value prior to randomization; 
Usage of a P-gp inhibitor that requires an edoxaban dose 
reduction (according to local edoxaban SmPC or IB as 
applicable); 
- 
Documentation of P2Y12 inhibitor other than clopidogrel and 
pre-declaration of the P2Y12 inhibitor to be prescribed (i.e., 
prasugrel, or ticagrelor); 
- 
Pre-declaration of the intended duration of ASA (100 mg 
once-daily) therapy (I - 12 months), if randomized to the 
VKA-based regimen; Please consider subject's medical 
history including components of the CHA2DS2-VASc score, 
HAS-BLED score (Appendix 17.5); 
 
Randomization: 
• 
If the reported INR::; 2.5 and reported CrCL 
15 mL/min, the 
IXRS accepts subject's eligibility and assigns the following: 
o subject identification number 
o the randomized treatment regimen 
o presence of edoxaban dose reduction requirement 
o kit numbers of the medications to be used 
• 
The day of randomization will be Day 1. 
• 
Urine sampling for pregnancy testing for women of childbearing 
potential (related to women who are pre-menopausal) (local 
laboratory) 
 
Immediately after randomization: 
The following activities are done after randomization and recorded in eCRF: 
• 
Collection of blood samples for the following central laboratory 
tests: 
- Safety samples for: liver function, serum chemistry, 
hematology and INR 
The samples are processed and sent to the central laboratory 
(Section 9.6 and 8.2, respectively). · 


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• 
The assigned treatment regimen and the proper daily dosing is 
explained to the subject including confirmation that the subject 
understands the proper daily dosing; 
• 
Collection of a 12-lead ECG recording (see section 9.8). The last 
post-index PCI ECG recorded before randomization can be used; 
• 
Collection of the  re- and _Rost-angiograms for the indeX=P_CL(se  e, 
_ 
section 10.1); 
• 
For subjects randomized to the edoxaban-based regimen: 
- 
Administer the first dose of edoxaban and of study P2Y12 
inhibitor according to Section 5.3.2 and 5.5.2, respectively. 
• 
For subjects randomized to the VKA-based regimen: 
- 
Administer the first dose of VKA, of study P2Y12 inhibitor 
and of ASA according to Section 5.4.2, 5.5.2 and 5.6.2. 
 
At hospital discharge or at the outpatient clinic: 
. • Dispensation of assigned study medication and of the medication 
log to the subject; Medication may be distributed to patients in an 
unbranded bag for convenience. 
• 
Instruction is provided to the subject to bring all study medications 
including anticoagulant and antiplatelet medications to each visit as 
well as the filled in medication log; 
• 
Schedule the next.on-site visit through the IXRS (i.e. Visit 2 at 1 
Month). 
 
Information to be recorded in the eCRF: 
• 
The following information is recorded in the eCRF: 
o Th date and timing of the first'dose of each study medication 
o All determined INR values and dose adjustments to reach target 
INR range of 2.0- 3.0 inclusive; 
o Significant physical findings under medical history; 
o Medical history including components of the CHA2DS2-VASc 
score, HAS-BLED score (Appendix 17.5) and past history of 
bleeding events; 
o All medications the subject was taking within 30 days prior to 
randomization (including medications given befo e and during 
the PCI procedure) see section 5.10; 
o Obtain a copy of the PCI procedure report and record 
information about index-procedure (e.g. but not limited to 
vascular access, lesions treated, stents used, procedure result); 


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o Local laboratory cardiac enzymes before and after index-PC!, if 
available (the closest to the index-PC! procedure and the most 
recent prior to randomization, respectively). 
- 
Consider collecting (it is not necessary to wait for these test 
results before randomizing the subject): 
- Cardiac troponin (cTn) 
  
_,.,,.r,,ea  .tins: ki nase_MB_isoform_(C KMB ,_     
_ 
  
 
o Last local laboratory test results , done post-index PCI: 
- Hemoglobin (Hgb) 
Platelet count 
- WBC (with differential if elevated) 
Total bilirubin (if elevated, determine 
conjugated/unconjugated bilirubin fraction) 
o Local laboratory test results, if available (the closest to the 
index-PC! procedure). 
- Cholesterol, total 
- Triglycerides 
o Vital signs 
 
6.2. 
Treatment Period 
Dates for all visits following the randomization visit are calculated to occur in 
relation to the randomization visit, with the <late of randomization being Day 1. 
 
 
6.2.1. 
On-site Visits: 1, 3, 6, and 9 Months (±7days) or unscheduled 
The following activities and/or assessments are performed at each on site visit: 
• 
Collection of blood samples for the following central laboratory 
tests: 
- Safety samples for: liver function, serum chemistry, 
hematology, INR. 
The samples are processed and sent to the central laboratory 
(Section 9.6). 
• 
Urine sampling for pregnancy testing for women of childbearing 
potential (related to women who are pre-menopausal) (local 
laborato·ry) 
• 
Dispensation of the assigned study medication and of the medication 
log to the subject; Medication may be distributed to patients in an 
- unbranded bag for convenience. 
• 
The assigned treatment regimen and the proper daily dosing is 
_ 
explained to the subject including confirmation that the subject 
understands the proper daily dosing; 
• 
Collection of a 12-lead ECG recording (see section 9.8); 


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- 
Local laboratory INR are determined for subjects randomized to 
VKA; 
- 
Instruction is provided to the subject to bring all study.medications 
to each visit, including edoxaban or VKA, P2Y12 antagonist, and 
ASA if applicable as well as the filled in medication log; 
  
 
  
  • _ T.heJollo_wing_infor m ation _is_obtai necloLrecorded_in_theJ XRS:.- - - - - - ---- 
o 
Local laboratory .CrCL; 
o 
Kit assignment for edoxaban or VKA, P2Y12 antagonist, and 
ASA study medications as needed; 
o 
. Discontinuation of ASA treatment (1-12 months), according 
to pre-declaration at randomization 
oNext on-site visit is scheduled (i.e. Visit 4, 3 Months; Visit 7, 6 
Months; Visit 10, 9 Months). 
 
 
- 
The following information is recorded in the eCRF: 
' 
' 
o 
·For subjects on VKA, all determined INR values 
and dose adjustments; 
o 
Any interruptions or dose adjustments of all study anticoagulant 
and antiplatelet dnigs with the date of last dose and the date of 
the first dose of resumption of drug (Section 5.7). Record this 
for each of the following separately: 
Edoxaban or VKA 
- 
P2Y12 antagonist 
- 
ASA 
oDate of the final dose of ASA in line with pre-declaration at 
randomization; 
o 
Concomitant medications; 
o 
All endpoints and all AEs experienced by the subject since the 
last visit. 
- 
Endpoint and other.event reporting occur throughout the 
study as soon as site personnel learn of the endpoint/event. 
In case of a suspected study endpoint, an additional 
assessment for subject compliance to the assigned regimen 
must be performed. 
- 
For subjects who experience a stroke event after 
randomization, the Investigator evaluates the residual 
disability by modified Rankin score 3 months after the onset 
of stroke (see Section 0). 
- 
Any treatments (drug and non-drug) given for endpoint 
events and AEs since the last visit. 


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Any h9spitalizations, coronary or vascular intervention or 
major coronary surgery (e.g. PCI or CABG procedures) 
since the last visit. 
Data on non-protocol driven outpatient physician or nurse 
visits, emergency room visits, or the use of long-term care, 
rehabilitation, or skilled nursing facilities related.to bleeding, 
-   -   -   -  -  - 
srrol<e-;SEE, myocaraiarinfarction, or stent thrombosis since 
the last visit. 
o 
Vital signs 
o 
Accountability of unused tablets of dispensed for edoxaban, 
P2Y12 antagonist, and ASA; 
 
6.2.2.  
Telephone Assessments: 2, 4, 5, 7, 8, 10 and 11 Months(± 7 days) 
The following assessments are performed during each telephone assessment: 
• 
The following information is recorded in the eCRF: 
- 
Documentation of the most recent INR for subjects randomized 
to VKA; 
- 
Any interruptions or dose adjustments of all study anticoagulant 
and antiplatelet drugs with the date of last dose and the date of 
the first dose of resumption of drug (Section 5.7). Record this 
for each of the following separately: 
Edoxaban or VKA 
P2Y12 antagonist 
- 
ASA 
- 
Concomitant medications; 
- 
All endpoints and all AEs experienced by the subject since the 
last visit/telephone assessment. · 
Endpoint and other event reporting will be done throughout 
the study as soon as site personnel learn of the 
endpoint/event. In case of a suspected study endpoint, an 
. 
additional assessment for subject compliance to the assigned 
regimen must be performed. 
Any treatments (drug and non-drug) given for endpoint 
events andAEs since the last visit/ telephone assessment. 
- 
Self-conducted pregnancy tests for women of childbearing 
potential (related to women who are pre-menopausal) 
 
• 
Next telephone assessment or on-site visit is scheduled, as 
applicable. 


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6.2.3. 
On-site Visit: 12 Months± 7 days (End-of-Treatment) 
The following will be performed for all subjects aJ the End-of-Treatment Visit 
(EOT): 
• 
Collection of blood samples for the following central laboratory 
tests: 
  
-,Safety samples fo   r:J   i y_er_functiorn  serum chemistYr-- ,,  ------------------------------------------- ­ 
 
hematology and INR 
The samples are processed and sent to the central laboratory 
(Section 9.6). · 
• 
Urine sampling for pregnancy testing for women of childbearing 
potential (related to women who are pre-menopausal) (local 
laboratory) 
• 
Dispensation of the transition study medication; 
• 
The transition medication and the proper daily dosing is explained 
to the subject including confirmation that the subject understands 
the proper daily dosing; 
• 
Collection of a 12-lead ECG recording (see section 9.8). 
• 
Local laboratory INR are determined for subjects randomized to 
VKA; 
• 
The following information is obtained or recorded in the IXRS: 
o Local laboratory CrCL; 
- 
Transition from assigned study regimen to an appropriate 
therapy (Section 5.3.3 and 5.4.4) 
• 
The following information is re orded in the eCRF: 
o For subjects on VKA, all determined INR values and dose 
adjustments; 
o Date and time·of the final dose for each of the study drugs; 
o Any interruptions or dose adjustments of all study anticoagulant 
and antiplatelet drugs with the date of last dose and the date of 
the first dose of resumption of drug (Section 5.7). Record this 
for each of the following separately: 
Edoxaban or VKA · 
- 
P2Y12 antagonist 
- 
ASA 
o Concomitant medications; 
o All endpoints and all AEs experienced by the subject since the 
last visit. 
- 
Endpoint and other event reporting occur throughout the 
study as soon as site personnel lefill} of the endpoint/event. 


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In case of a suspected study endpoint, an additional 
assessment for subject compliance to the assigned regimen 
must be performed. 
For subjects who experience a stroke event after 
randomization, the investigator evaluates the residual 
disability by modified Rankin score at the time of discharge 
-   -   --  -   -   -   -   -   -   -   - -  - 
from the-hospital-csee-Sectioff 0 \--. - - - - - - - - - - - - - - 
Any treatments (drug and non-drug) given for endpoint 
events.and AEs since·the last visit. 
Any hospitalizations, coronary or vascular intervention or 
major coronary surgery (e.g. PCI or CABG procedures) 
since the last visit. 
Data on non-protocol·driven outpatient physician or nurse 
visits, emergency room visits, or the use of long-term care, 
rehabilitation, or skilled nursing facilities related to bleeding, 
stroke, SEE, myocardial infarction, or stent thrombosis since 
the last visit. 
o Vital signs 
o Accountability of unused tablets of dispensed for edoxaban, 
P2Y12 antagonist, and ASA 
• 
For subjects still on edoxaban or VKA, the final on-site visit is 
scheduled (i.e. Visit 14, 1 Month post-EOT); 
• 
The EOT visit is performed for subjects who have a premature 
discontinuationof their assigned OAC-based regimen or who have 
modified their IC after randomization with full withdrawal of IC 
(see details section 6.5).For these subjects, the scheduling of the 
EOT remains unchanged (i.e. 12 months± 7 days). In such· cases, 
the EOT visit is the end-of-study visit/contact. 
 
 
6.2.4. 
Additional Visits/Assessment in the VK.A-based regimen 
For subjects randomized to the VKA-based regimen, INR management may be 
performed by the Investigator, the subject's primary care physician or other private 
physician, or at a specialized anticoagulation clinic or patient self-monitoring. 
Documentation of all INR values must be maintained, including INR tests 
performed outside oflnvestigator'ssite. It is the responsibility of the Investigator 
· or designee to enter all INR results into the eCRF. 
The Investigator or designee will measure or collect (by email or fax) the subjec 's 
INR value(s) and VKA dose information at least every month. Separate 
documents provided to the sites will inform the Investigator of the recommended 
frequency of INR monitoring. 
· 
For Investigators who are managing INR for subjects assigned to VKA, 
unscheduled site visits are pennissible to achieve and maintain an INR in the target 
therapeutic range (2.0 - 3.0). The procedures performed at such an unscheduled 


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visit are identical to those described above for regular on site visits (see section 
6.2.1). 
 
 
6.2.5. 
. Missed Follow up Visits 
Every effort should be made to ensure subjects return for their on-site visits. If the 
- - - 
sub-Jecr'isu naole to return for an on-site visit-;-tfie lnves tlgator, or des1gnee, mus 
document _in the patient record the reason the subject was unable to complete the 
visit. The Investigator should also make every effort to contact the subject, within 
the visit window, to collect the subject's vital status as well as information related 
to potential adverse events, safety data, and hospitalizations. 
 
 
6.3. 
Post-treatment Period 
 
6.3.1. 
On-site Visit: 1 month post-EOT (± 7 days) 
All subjects on edoxaban or VKA at 12 months (EOT visit), have a visit planned 
30 days thereafter. 
Subjects who prematurely discontinued their assigned OAC will not require an 
additional follow-up visit or telephone contact after the End of Study Visit apart 
from patients withdrawn due to AEs (see section 4.3.1 and 43.2). 
 
 
The following wUl be performed at the post-EOT visit: 
• 
Record targeted concomitant medications; 
• 
Collection of a 12-lead ECG recording (see section 9.8); 
• 
Vital signs; 
• 
Record all endpoints and all AEs experienced by the subject since 
the la,st visit. 
- 
Endpoint and other event reporting (including 
hospitalization) will be done throughout the study as soon as 
site personnel learn of the endpoint/event; For subjects who 
experience a stroke event after randomization, the 
Investigator will evaluate the residual disability by modified 
Rankin score at the time of discharge from the hospital (see 
Section 17.7). 
- 
Record any treatments (drug and non-drug) given for 
endpoint events and AEs since the last visit. 
- 
Record any hospitalizations, PCI procedures, and CABG 
procedures since the last visit. 


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6.4. 
Protocol Deviations 
The Investigator conducts the study in compliance with the protocol agreed to by 
sponsor and, if required, by the regulatory authority(ies) and by the EC. 
Actio_ns taken to eliminate immediate subject hazard(s) that deviate from any 
protocol procedures are marked/ flagged as a deviation. The sponsor and site 
monitor must be notified of all intended or unintended deviations to_tht_pi:_oto _co  l. 
 
  
 
• (e.g., inclusion/exclusion criteria, dosing) on an expedited basis. The Investigator, 
or person designated by the Investigator, should document and explain any 
deviation from the approved protocol and notify the EC of any protocol deviations 
in accordance with local procedures. 
Even if a subject was ineligible or inadvertently received the incorrect drug or 
dosage, discontinued or interrupted the assigned treatment regimen, or refused to 
· further undergo on-site visits, clinical follow-up data should still be collected up to 
12 months after randomization (EOT). 
 
6.5. 
Modification of IC after Randomization 
Subjects are scheduled to have regular study contacts every month until the 12- 
month EOT visit is completed. 
In accordance with the Declaration of Helsinki and other applicable regulations, a 
subject has the right to withdraw consent from study participation at any time and 
for any reason without prejudice·to his or her future medical care by the physician 
or at the institution. 
This protocol makes a distinction between request to discontinue (1) any or all 
study medication, (2) on site visits, (3) telephone contacts, (4) collection of 
clinical follow-up_ data, (5) collection of vital status and (6) full withdrawal ofIC. 
All subjects are followed for 12 months irrespective of changes in the 
antithrombotic regimen. Henceforth, during interruption or following 
discontinuation of study medication, subjects continue to have regular study visits 
or telephone assessments until the 12-month EOT visit is completed. 
If the subject cannot return for an in-person visit, a telephone visit is scheduled 
unless subject requests not to be contacted by telephone. Collection of available 
clinical data or vital status, either at the interventional centei;, at the referring 
hospital, with the genera-l practitioner,or the municipal registries continues unless 
explicitly disallowed by subject. 
Collected data up to the date of full withdrawal ofIC are used in the final analysis. 
Records in the eCRF document modifications to the IC as detailed above (incl. 
level and date of modification or withdrawal). 
 
 
6.5.1. 
Subjects Lost to Follow-Up 
All subjects should be encouraged to return for protocol-required on-site visits or 
telephone assessments for evaluation during the clinical follow-up. If a subject is 
unable to return for a clinic visit, subject should be contacted by telephone.to 
obtain subject required information. All attempts should be documented in the 


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sour_ce documents. If the subject does not respond to telephone calls, th·en the 
Investigator must send a certified letter to the subject. Only after failing to contact 
the subject at.the final follow-up visit will the subject be considered lost to follo ­ 
up after last contact except for mortality if available via municipality registries. It 
must be a high priority to obtain at1east survival data on all subjects lost to follow­ 
up. When a subject is lost to follow-up a study End-of-Study Form is completed. 
 
 
6.6. 
End of Trial Definition 
All subjects on OAC study medication (edoxaban or VKA) at 12 months, have a 
contact planned 1 month after the EOT visit, to collect data on targeted 
concomitant medications, SAEs, and other events of interest. The final contact is 
either the scheduled EOT visit at 12 months or the post-treatment follow-up visit 
scheduled at 13 months. The study completion is reached as soon as the final 
contact of the last subject is performed in all centers and in all participating· 
countries. 


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7. 
OUTCOME ASSESSMENTS 
 
7.1. 
Primary Endpoint 
The primary endpoint is the composite of major or clinically relevant non-major 
bleeding (MCRB) defined according to the ISTH-defined bleeding definitions, 
analyzed as time to first occurrence of any component. 
 
 
7.2. 
Secondary Exploratory Endpoints 
The secondary endpoints are defined as: 
- 
Main efficacy endpoint (MEE), defined as the composite of cardiovascular 
(CV) death, stroke, systemic embolic events (SEE), myocardial infarction 
(MI) and definite stent thrombosis. 
- 
Net clinical benefit (NCB), defined as the composite of CV death, stroke, 
SEE, MI, definite stent thrombosis and ISTH-defined major bleeding. 
- 
Main thromboembolic event, defined as composite of cardiac or 
thromboembolic death (thromboembolic death considered to be 
thromboembolic in origin (including thromboembolic stroke, pulmonary 
embolism, any other systemic embolism), ischeniic stroke, SEE, MI and 
definite stent thrombosis. 
ISTH-defined major bleeding 
- 
Any bleeding defined as the composite of major, clinically relevant non­ 
major and minor bleeding (ISTH definition) 
Symptomatic intracranial hemorrhage (ICH) 
- 
Composite of stroke and SEE 
Composite of all-cause death, stroke, SEE, MI and definite stent thrombosis 
Composite of CV death, MI and definite stent thrombosis 
- 
The single components of the composite primary and secondary endpoints 
mentioned above are explored, as well as specific subcategories (e.g., 
hemorrhagic, ischemic and undetermined stroke) 
Safety paramete.rssuch as _(serio 
us) adverse events, laboratory parameters, 
ECG and vital signs. 
 
All secondary endpoints are analyzed as time to first occurrence of any of its 
components. 
Bleeding events are also classified acco ding to Bleeding Academic Research 
Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI) 
classifications for descriptive purposes only. All suspecte9 bleeding events are 
adjudicated by the CEC in a blinded manner. 
All events are also sub-categorized into fatal and non-fatal. 


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For all endpoints blindly adjudicated by the CEC, the CEC's interpretation 
prevails and is used in the statistical analyses. 
 
 
7.3. 
Endpoint definitions 
All suspected endpoint events are adjudicated by an independent CEC (see section  
 
  
   
17.1.2) without knowledge of the actual assigned treatment. The adjudication . 
criteria are mentioned below. Further details on these definitions and how they 
will be assessed are provided in the CEC Charter. Th requirements for collecting 
and submitting the source documents for appropriate adjudication of the reported 
primary and secondary endpoint events will be provided to the sites/Investigators 
separately in the Study Operations Manual. 
For all endpoints blindly adjudicated by the CEC, the CEC's interpretation 
prevails and is used in the statistical analyses. 
 
7.3.1. 
Bleeding 
Bleeding will be classified according to the 18TH definitions (see section 17 .3). 
Bleeding events will also be classified according to BARC (14) and TIMI (21, 22) 
classifications for descriptive purposes only. 
 
7.3.2. 
Components of MEE 
The following endpoint definitions will be applied: 
CV death, defined as cardiac or vascular death according to Academic 
Research Consortium (ARC) (23) .. 
- 
Thromboembolic death (thromboembolic death considered to be 
thromboembolic in origin (including thromboembolic stroke, pulmonary 
embolism, any other systemic embolism), defined as CV death excluding 
fatal bleeding defined as BARC sub-category 5 (14). 
- 
A stroke is defined as an abrupt onset, over minutes_ to   hours, of a focal 
neurological deficit in the distribution of a single brain artery that is not due 
to an identifiable nonvascular cause (i.e., brain tumor or trauma), and that 
either lasts at least 24 hours or results in death within 24 hours of onset 
(13). Stroke will be sub-divided into ischemic, hemorrhagic or 
indeterminate. Stroke is categorized in disabling and non-disabling stroke 
using the mRS score. 
TIA is defined as an abrupt onset, over minutes to hours, of a focal 
neurological deficit in the distribution of a single brain artery, that lasts less 
than 24 hours and is not due to an identifiable non-vascular cause (i.e., 
brain tumor or trauma) and does not satisfy the stroke definition above. (13) 
An SEE is defined as an arterial embolism resulting in clinical ischemia, 
excluding the central nervous system (CNS), coronary and pulmonary 
arterial circulation (13). 
Spontaneous MI according to Universal MI definition (24) and 
periproced_ural MI according to the SCA! MI definition (25) 


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Stent thrombosis according to ARC (23) 
 
7.3.3. 
Other 
lntracranial hemorrhage is a sub-category of ISTH major in a specified critical 
organ, to be determined by the CEC. 
 
 


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8. 
PHARMACOKINETIC ASSESSMENTS . 
 
8.1. 
Pharmacokinetic (PK) Variable(s) 
Not applicable. 
 
8.2. 
Non-genetic biomarkers and Exploratory Variable(s) 
Not-applicable (please-refer to-section- n 2) 


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. 9. 
SAFETY ASSESSMENTS 
Safety assessments that are components of the study endpoint assessments (e.g. 
bleeding endpoints) are detailed in Section 7.3 and must be collected in the 
AE/Outcome eCRF page, 
 
 
- -    9.1. 
Adverse Events (AEs) 
 
9.1.1. 
Definitions 
 
9.1.1.1. 
Adverse Event (AE) 
Any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding for example), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
9.1.1.2. 
Unexpected Adverse Event 
An unexpected AE (uAE) is an AE, the nature or severity of which is not 
consistent with the reference safety information of any of the study medication. 
The designation of expected or unexpected must be decided from the perspective 
of previously described AEs, not on the basis of what might be anticipated from 
pharmacological properties of a medicinal product. The investigator can provide 
his judgment on the expectedness/unexpectedness of a reported AE to the sponsor 
and this will be taken into account for the sponsor's judgment of expectedness. 
However, the final determination of expectedness is the responsibility ofDSE and 
not the investigator. 
9.1.1.3. 
Expected Adverse Event 
An expected AE is an event which is described in the reference safety information 
of the study drugs in nature, severity or incidence. 
 
 
9.1.1.4. 
Serious Adverse Event (SAE) 
An SAE or reaction is any untoward medical occurrence that at any dose: 
• 
results in death. 
• 
is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death 
if it were more severe. 
• 
requires 
inpatient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation. 
• 
results in persistent or significant disability/incapacity. 
• 
is a congenital anomaly/birth defect. 


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OR 
• 
is any other medically important condition (see below). 
 
 
Note: Medical and scientific judgement should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
-   - -c;ve nts-that-may-not-be-immediately-life-threateningor-result-in-death-or  --------------------------------------- ­ 
hospitalisation, but may jeopardise the subject or may require intervention to 
prevent.one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples include allergic bronchospasm, 
convulsions, and 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. 
. 
• 
Treatment requiring hospitalizationsfor pre-existing conditions which do 
not worsen in severity are not SAEs. 
 
9.2. 
Classification for AE assessment 
 
 
9.2.1. 
Severity of Adverse Events 
The severity of an AE is graded as follows: 
Mild: 
Discomfort noted, but no disruption of normal daily activity. 
Moderate:Discomfort sufficient to reduce or affect normal daily activity. 
Severe: 
 
Inability to work or perform·normal daily activity. 
 
9.2.2. 
Relationship of Adverse Events 
The Investigator should assess causal relationship between an adverse event and 
the assigned anticoagulant-based regimen (i.e., edoxaban-based or VKA-based) 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 the assigned 
anticoagulant-based regimen administration, and cannot be 
reasonably explained by the subject's clinical state or other factors 
(e.g., disease under study, concurrent diseases, and concomitant 
medications). 
The AE follow_ s a reasonable tempora- l sequence from the assigned 
anticoagulant-bas d regimen administration, and is a known 
reaction to any of the study medications (i.e. the components of each 


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study regimen) under study or its chemical group, or is predicted by 
known pharmacology. 
• 
2 = Not Related: 
The AE does not follow a reasonable sequence from the assigned 
. anticoagulant-based regimen administration, or can be reasonably 
expla ned by the subject's clinical state or other factors (e.g., disease 
- - - - - - - - - under study;-concurrent-diseases affd concomitant medications)-. --- 
 
 
9.2.3. Action Taken Regarding the Assigned Antithrombotic Regimen 
For each drug of each antithrombotic regimen (either, edoxaban and clopidogrel in 
the edoxaban-based regimen or VKA, P2Y12 inhibitor and ASA in the VKA-based 
regimen), the action taken after an AE must be recorded in the eCRF as delineated 
below: 
1 = Dose Not Changed: No change in dosage was made. 
2 = Drug Withdrawn: Permanently stopped. 
3 = Dose Reduced: The dosage was reduced. 
4 = Drug Interrupted: Temporarily stopped. 
5 = Dose Increased: The dosage was increased. 
 
 
9.2.4. Other Action Taken for Event 
1 = None: No treatment was required. 
2 = Concomitant medication required: Prescription and/or over-the­ 
counter medication were requir d to treat the adverse event. 
3 = Concomitant medication permanently discontinued: Prescription 
and/or over-the-counter medication other than the assigned 
anticoagulant-based regimen was permanently discontinued due 
to the adverse event. 
4 = Concomitant medication temporarily interrupted: Prescription 
and/or over-the-counter medication other than the assigned 
anticoagulant-based regimen was temporarily interrupted due to 
the adverse event. 
5 = Other. 
 
9.2.5. AE Outcome 
1 = Recovered/Reso lved: The subject fully recovered from the 
adverse event with no residual effect observed. 
2 = Recovered/Reso lved with Sequelae: The residual .effects of the 
adverse event are still present and observable. Include 
sequelae/residual effects. 


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3 = Not Recovered/Not Resolved: The adverse event itself is still 
present and observable. 
4 = Fatal 
5 = Unknown 
 
 
Tne Investigator should follow subjects with AEs until the event has resolved or 
the condition has stabilized. In case of unresolved adverse events including 
significant abnormal laboratory values at the end of study assessment, these events 
will be followed up until resolution or until they become clinically not relevant. 
 
 
9.3. 
AEs of Special Interest 
9.3.1. Combined Elevations of Aminotransferases and Bilirubin 
There was no clinically concerning signal of drug-induced liver injury associated 
with edoxaban based on the extensive global phase 3 experience involving over 
34,100 edoxaban subject-years exposure (with median drug exposure of ~2.5 
years among ~14,000 edoxaban subjects). However, there will be ongoing 
monitoring of hepatic events, including combined elevations of aminotransferases 
and bilirubin (ALT or AST> 3 x ULN with simultaneous TBL > 2 x ULN), 
particularly those without evidence of cholestasis (ALP 2: 2xULN is considered 
evidence of possible cholestasis) and without alternative etiology for 
hepatocellular damage. 
Combined elevations of aminotransferases and bilirubin, either serious or non­ 
serious and whether or not causally related, should always be reported to the 
Sponsor as soon as possible following the procedures outlined in Section 9.5 for 
SAE reporting. 
In cases ofliver laboratory abnormalities, or evidence of liver dysfunction, it is 
important to ensure that the etiology of liver injury is identified and study subjects 
are·monitored until the liver laboratory assessments return to normal. 
 
 
9.3.2. Reporting of Pregnancy/Exposure in Utero 
The sponsor or designee must be notified of any subject that becomes pregnant 
while participating in a clinical study. 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 subject, which occurs during the study,. 
If any study subject or their partner becomes or is found to be pregnant while 
receiving, or within 30 days of discontinuing the investigational product, the 
Investigator should contact the Medical Monitor to discuss subject management 
and receive further information. Notification of the pregnancy, should be 
submitted in the eCRF (AEs of special interest) within 24 hours and reported using 
Exposure in Utero Reporting form (paper fori:n). 


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If it is the partner, rather than the subject, who is found to be pregnant, the 
Exposure in Utero Reporting Form should be completed with the subjects' 
identification number, and year of birth. Details regarding the partner should be 
entered in the narrative section of the Exposure in Utero Reporting form if a 
consent of the trial subject's partner has been obtained bythe Investigator. 
If the pregnancy is to be terminated, the anticipated date of termination should be 
- - J)re vi Eie Ei-,--I f:-the - preg nancy-ends-for-any reason-bt;!fore -t he-anticipated-da,te the ----------------------------- ­ 
Investigator should notify the Sponsor. If the outcome of the pregnancy meets the 
criteria for immediate classification as a 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 repo1ting an SAE. At the completion of the pregnancy, the 
Investigator will document the outcome of the pregnancy in a follow-up Exposure 
in Utero Reporting Form. · 
 
 
9.4. 
Timing of Adverse Event Reporting 
All AEs must be recorded and reported from the stated starting point of the 
clinical trial (immediately after signing IC) including AEs talcing place during the 
administration of other drugs. Even if the subject has not yet received the 
investigational study regimens, untoward medical occurrences have to be treated 
as AEs. 
The period of AE reporting is defined as follows: 
AEs that occur within 30 days after the last dose of the assigned study 
anticoagulant-based regimen which are reported to the Investigator (regardless of 
the date of a follow-up visit) must be recorded in the eCRF. 
 
9.5. 
Reporting SAEs/AEs 
 
9.5.1. 
Documentation 
To effectively evaluate the safety profile of the anticoagulant-based regimens, this 
study will report all (S)AEs occurring after the subject signs the IC and up to 30 
days after the last dose of the assigned anticoagulant-based regimen, whether 
observed by the Investigator or reported by tlie subject. All AEs will be recorded 
on the AB/Outcome eCRF page and include: 
• 
Any components of the study endpoint assessments (see Section 7); 
• 
AE that meet seriousness criteria (see Section 9.2.1); 
• 
AE that result in interruption or discontinuation of the assigned anticoagulant­ 
based regimen; 
• 
AE that meet the criteria for AE of special interest (see Section 9.3); 
• 
Any other AE. 
All laboratory results and vital signs should be evaluated by the Investigator 
regarding clinical significance. Isolated abnormal laboratory results or vital sign 
findings that are not part of a diagnosis should be reported as AEs or SAEs. 


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Medical conditions (including laboratory values/vital signs that are out of range) 
that were diagnosed or known to exist prior to IC will be recorded as par1 of 
medical history. 
All SAEs are to be reported according to th.e procedures in Section 9.5.2 below. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is 
unavailable, report the primary sign or symptom as the AE or SAE term with 
- -  additional-details-included-in-the narrative-until-the diagnosis-becomes-availabl,,.  
_ 
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 serious 
adverse event (diagnosis or symptom requiring hospitalization). 
AEs may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit. Subjects should be questioned in a 
general way, without asking about the occurrence of any specific symptoms. The 
Investigator must assess all AEs to determine seriousness, severity, and causality, 
in accordance with the definitions in Section: 9.2. The Investigator's assessment 
must be clearly documented in the site's source documentation with the 
Investigator's signature. 
 
In case of an occurrence of an (S)AE, the Investigator applies the following rules: 
• 
Ensure appropriate medical treatment and decide whether to discontinue 
or interrupt any of the study medications. 
• 
Complete the initial AE/Outcome eCRF page upon event awareness. 
• 
Record the event, its management, and outcome in the eCRF page. 
• 
For SAEs, report in the eCRF within 24 hours of receiving knowledge 
of the occurrence.. In the event that all the required information is not 
available, the information which is available is to be sent without delay 
(within 24 hours), and the outstanding data relayed as soon as available 
thereafter. Answer any queries related to the reported SAE as soon as 
po sible. 
• 
For AEs of special interest, report within 24 hours of receiving 
knowledge of the occurrence as defined for SAEs above. 
• 
For AEs, obtain all data required incl. any information which, is only 
available after considerable delay (i.e. hospital reports, outcomes, 
resolution end dates), as soon as available. 
• 
Components of the study endpoint assessments which result in death 
must be reported as SAEs within 24 hours of the Investigator's 
awareness. 
 
 
9.5.2. 
Notifying Regulatory Authorities, Investigators and IRB/IEC, 
Detailed SAE processing, distribution and reporting will be laid out in sponsor's 
SAE Flow Plan. 


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Sponsor and/or ARO/CRO will inform Investigators, IRBs (Institutional Review 
Board)/IECs (Independent Ethics Committees), and regulatory authorities of any 
Suspected Unexpected Serious Adverse Event Reactions (SUSARs) occurring in 
. the study or other sponsor studies of the investigation·a1product (excluding waived 
study endpoint events per Section 6.6), as appropriate per local reporting 
requirements. 
- 
- 
- 
--1  n-the--European-Bnion-countries;-it-is the-Sponsor's-i-esponsibilityio1epo 
SUSARs to regulatory authorities and IECs. 
Study endpoints are clinically anticipated events in AF subjects receiving 
antithrombotic therapy and will be periodically reviewed by the DSMB in a 
blinded manner to ensure prompt identification of any clinically concerning safety 
issues. 
 
9.6. 
Clinical Laboratory Evaluations 
Refer to the Laboratory Manual for detailed instructions of sample collection, 
storage, and shipment. The results will be reviewed and compared to the central 
laboratory's normal ranges. The visits at which these samples will be collected are 
shown irt the schedule of assessments (Appendix 17.9). 
The following safety laboratory evaluations are performed in individual blood 
samples. 
• 
Liver Function Panel 
o Total bilirubin (conjugated/unconjugated.performed when total 
serum bilirubin 2: 2 mg/dL) 
o Alanine transaminase (ALT) 
o Aspartate transaminase (AST) 
o Alkaline phosphatase (ALP) 
• 
Serum Chemistry Panel 
o Creatinine 
• 
Hematology Panel 
o White blood cell (WBC) count with differential if elevated 
o Hemoglobin 
o Platelet courit 
• · INR 
• 
Urine Sampling (only at baseline and follow up for pregnancy testing). 
Pregnancy tests will be provided for female patients with childbearing 
potential (related to women who are pre-menopausal) to be performed at 
home in case of visits by phone. 
 
All other assessment are collected from local laboratory"results for tests done as 
part of routine care. Local laboratory assessments are used for parameters required 


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to verify eligibility and for parameters that re uire monitoring according to local 
routine. 
 
9.7. 
Vital Signs 
The following parameters are recorded for vital signs: 
• 
Blood pressure (BP), sitting diastolic and systolic BP 
• 
Weight 
• 
Height (only at baseline) 
 
9.8. 
Electrocardiograms 
Twelve-lead ECG are collected according to the schedule of assessments (section 
17.9). Investigational sites will utiliz-e local ECG equipment and record pertinent 
information in the eCRF while preserving all recorded ECG tracings as subject 
source documentation. 
 
9.9. . 
Physical Findings 
The Investigator or a licensed team member performs targeted physical 
examination according to the schedule of assessments. This physical examination 
cons_ists of assessment of each of the relevant (including but not limited to cardiac, 
neurologic, pulmonary, G_I) major body systems. In order to be able to detect any 
renal impairment, the Creatine Clearance will be calculated. In addition, All 
information needed for the calculation will be collected in the eCRF. Any 
clinically significant findings must be recorded in the eCRF under.medical history 
at baseline and under AB/Outcome until the subject's final contact. 


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10. 
OTHER ASSESSMENTS 
 
10.1. 
Coronary angiograms 
The pre- and post-index PCI coronary angiograms are recorded according to the 
standard of care. 
 
-   - 
 1=-0.=,_.,.2 '.- - 
Hosp_italisations, 
 
In
addition to the standard SAE data collected for hospitalisation as described in 
Section 9.1.1.4, additional data will be collected for hospitalisations that are 
reported for one of the following reasons: 
• 
Bleeding 
• 
Stroke 
• 
SEE 
• 
Myocardial infarction 
• 
Stent thrombosis 
Data on length of hospital stay (admission and discharge dates), admission unit 
(e.g_. ICU), admission diagnosis and discharge status will be collected for any of 
the above hospitalisations. 
In addition, data on non-protocol driven outpatient physician or nurse visits, 
emergency room visits, or the use of long-term care, rehabilitation, or skilled nursi_ng
 
facilities related to bleeding, stroke, SEE, myocardial infarction, or stent 
thrombosis will be collected throughout the study. 


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11. 
STATISTICAL METHODS 
 
11.1. 
Analysis Sets 
 
11.1.1. 
Intention-to-treat analysis set 
The Intention-to-treat Set (ITT) consists of all randomized subjects irrespective 
  
 whether they_recei "-ed_a si ngle_dose _of  the    randomi 
zeclstu 
cLy..regimen-   o L no  ..  
   
 
Analyses will be based c;m the randomized treatment regimen even if a subject 
inadvertently receives the incorrect drug(s) or dosage or has his/her edoxaban dose 
adjusted (decreased/increased) one or more times during the study. Th reference 
date for consideration of endpoints is the date and time of randomization. 
 
11.1.2. 
Modified Intention-to-treat analysis set 
The modified Intention-to-Treat Analysis Set (mITT) consists of all randomized 
subjects who received at least one dose of study edoxaban or study VKA 
according to IXRS assignment. 
Analyses will be based on the randomized treatment regimen even if a subject 
inadvertently receives the incorrect drug(s) or dosage or has his/her edoxaban dose 
adjusted (decreased/ increased) one or more times during the study. The reference 
date for consideration of endpoints is the date and time of first intake of study 
edoxaban or study- VKA. 
11.1.3. 
Per Protocol analysis set 
The Per Protocol Analysis Set (PP) consists of all·randomizedsubjects who 
received at least one dose of the study regimen according to IXRS assignment and 
do not have any of the following major protocol violations: 
• 
A major violation of the inclusion criteria 
o No stent placement 
o No successful PCI (see section (definjtion)) 
o Planned further (staged) PCI 
o NoAF 
o Known contraindication for OAC 
• 
An unequivocal violation of the exclusion criteria 
 
 
The list of major violations will be finaljzed before data base lock. The list and the 
exclusions will be confirmed in a blinded way, i.e. without knowledge of the 
randomized study regimen and of the clinical outcomes. 
 
Analyses will be based on the randomized treatment regimen, even if a subject 
inadvertently receives the incorrect drug(s) or dosage or has his/her edoxaban 
dosage adjusted (decreased/ increased) one or more times during the study. The 
reference date·for consideration of endpoints is t e date and time of first intake of 
study edoxaban or study VKA. 


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11.1.4. 
Safety analysis set 
The Safety (SAF) Analysis Set consists of all randomized subjects who received at 
least one dose of the study .edoxaban or study VKA according to IXRS 
assignment. 
Analyses will be based on the randomized treatment regimen, even if the subject's 
edoxaban dosage is adjusted after randomization, unless a subject inadvertently 
receives tlie incorrect arug(s) or aosage during the entire study, in which case the 
subject will be grouped accorqing to the treatment actually received. The reference 
date for consideration of endpoints is the date of first study.medication intake. 
Note: This SAF analysis set is identical to the mITT analysis set and will be used 
for the safety parameter·s (e.g. adverse events, vital signs, laboratory parameters, 
etc.) as described under section 9. 
 
11.2. 
General Statistical Considerations 
All analyses will.be performed on observed data only. No missing data will be 
imputed. Data on subjects who do not reach a specific endpoint will be censored in 
the corresponding statistical analyses. 
. Raw data will be presented with the exact precision (decimal points) with which it 
was collected. 
The p-values will be presented in the end-of-text tables exactly as they are in 
supporting statistical documents (4 decimal points). The text and in-text tables will 
display p-values with three decimal places, as long as, the decision for statistical 
significance will not be changed by rounding. 
The number of decimal places to display for calculated data will be determined by 
the scale of measurement. No decimal places will be displayed if the smallest 
calculated value is 2'.: 100; One (1) decimal place will be displayed when all 
calculated values are within the interval (10, 100), with 10 being inclusive; Two 
(2) decimal places will be displayed when all calculated values are within (1, 10), 
with 1 being inclusive; and so on for even smaller scales of measurement. 
Percentages will be reported with exactly one decimal place. 
For continuous variab)es, statistical summaries will include n (number of subjects 
with non-missing data), mean, median, standard deviation, minimum and 
maximum: Means and medians will be displayed to one more decimal places than 
the raw or calculated data; standard deviatio andother dispersion statistics will 
have two more decimal places; and minimum and maximum values will be 
displayed to the same number of decimai places as the raw or calculated data. 
For categorical variables, statistical summaries will include counts and 
percentages. Percentages will be reported with exactly one decimal place. In 
general, percentages are based on the total number of subjects with information 
available (ie non-missing data). For AE and incidence based analyses, percentages 
will be based on the total number of subjects in the analysis set of interest and in 
that treatment regimen. 
The statistical data analysis will be performed by a CRO under the guidance of the 
study biostatistician using SAS Version 9.3 or higher. 


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Definition of terms: 
'Overall Study Period': This period is <;iefined as the time from the reference date 
(date and time of randomization or date and time of first study edoxaban or study 
VKA intake) to Day 365. 
'Qvemll Study P-er-iod =I= 30 da ys': T his-perfod-is-defined -as-the-time-:from-thv ------------------- ­ 
reference data (date and time of randomization or date and time of first study 
edoxaban or study VKA intake) to Day 395. 
· 'Initial dose to Final Dose + 30 days': This period is defined as the time-period 
between the date and time of initial dose of study edoxaba·n or study VKA and the 
date and time of final dose of study edoxaban or study VKA plus 30 days, 
including study regimen interruptions. 
· 
 
 
Follow-up is censored at the last date of known follow-up status in subjects with 
incomplete follow-up. Investigators are instructed to complete follow-up as much 
· as possible irrespective of changes or discontinuation of study medication. 
When using the ITT analysis set, the reference date is the date and time of 
randomization, whereas in mITT and PP analyses, the reference date is the date 
and time of first intake qf stud·y edoxaban or study VKA. 
The main analyses of adjudicated primary and secondary exploratory endpoints 
(Section 7:1 and 7.2, respectively) will be based on ITT analysis set and takes the 
first adjudicated event during the 'overall study period' into account·.· 
However, in supplemental analyses, other combinations of analysis sets and 
analysis periods may be considered to evaluate the robustness of the main analyses 
on adjudicated safety or efficacy endpoints. Details on these analyses will be 
described in the SAP. 
· 
 
11.3. 
Study Population Data 
Subject disposition will be summarized for each randomized treatment regimen 
and in total for the ITT analysis set. The number of subjects for each defined 
analysis set by treatment regimen will also be tabulated. 
The demographic and baseline characteristics including baseline disease status 
will be summarized descriptively by treatment regimen for the ITT, mITT, PP and 
SAF analysis sets. 
Exposure to study medicatio·n (edoxaban, VKA, P2Y12 antagonist, and ASA) will 
be SllID;Jllarized using descriptive statistics by treatment regimen for the mITT, PP 
and SAF analysis sets. Interruptions and permanent discontinuations (see Section 
5.7) will be summarized by treatment group for the same nalysis sets. 
The time in therapeutic range (TTR) (INR: 2.0 to 3.0, inclusive) will be estimated 
for each subject randomized to the VKA-based antithrombotic regimen using the 
interpolation method of Rosendaal (26). 


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11.4. 
Statistical Analysis 
For each of the primary and secondary exploratory endpoints, appropriate 
summary statistics (e.g. event rate) including 95% CI will be provided. 
For each of the endpoints, the time from reference date to the first occurrence of 
an event (based on CEC adjudication), is analyzed using a Cox proportional 
hazard model with treatment regimen as a factor and all the stratificat'ion factors 
 
- 
- 
- - 
from the randomization (IXRS) as covariates, to provide point estimates and 95% 
Confidence Interval (CI) for the hazard ratio (HR). Depending on the analysis. 
period used in the statistical analysis, subjects without an occurrence of an event 
will be censored at the last date of the analysis period or at the last date of known 
outcomes status. The latter is determined an individual basis for subjects with 
incomplete follow-up. 
The parameter estimate p (= In (Hazard ratio), its standard error, p-value, and 95% 
Confidence Limits are calculated according to the maximum partial likelihood 
method (ML), with Breslow's approximation for ties (SAS PHREG procedure). 
For time to first event analyses based on the ' overall study period', cumulative 
event rates over time are summarized using the Kaplan-Meier method. 
11.4.1. 
Analysis of the prim ry endpoint 
The primary endpoint is defined as the composite of major or clinically relevant · 
non-major bleeding (MCRB) defined according to the ISTH-defined bleeding 
definitions (see section 7.3). 
There are two primary hypotheses for the primary endpoint_to be tested in this 
study. 
• The edoxaban-based antithrombotic regimen is non-inferior to the VKA-based 
antithrombotic regimen with regards to MCRB. 
• The edoxaban-based antithrombotic regimen is superior to the VKA-based 
antithrombotic regimen with regards to MCRB. 
These two hypotheses are tested in a hierarchical manner, non-inferiority followed 
by superiority to control the type-I error rate, with adequate power for each of the 
two hypotheses. 
· 
 
11.4.1.1. 
Test for non-inferiority 
The primary analysis to show non-inferiority will be based on first occurrence of 
an (adjudicated) MCRB that occurred during the 'overall study period' for all 
subjects belonging to the ITT analysis set and applying the aforementioned . 
statistical method. The edoxaban-based regimen will be considered non-inferior to 
the VKA-based regimen, if the upper boundary of the two-sided 95% CI for HR 
falls below 1.20. 
To evaluate the robustness of the primary analysis, the analysis will be repeated 
using the mITT and PP analysis set. In addition, the statistical results based on the 
following analysis periods: ' initial dose to final dose+ 30 days', 'overall study 
period+ 30 days' will be presented but should be interpreted in a more descriptive 
way. Results for other combinations of analysis sets and analysis periods may be 
presented if considered necessary. 


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11.4.1.2. Test for superiority 
The primary analysis to show superiority will be basec,1 on first occurrence of an 
(adjudicated) MCRB that occurred during the 'overall study period' for all 
subjects belonging to the ITT analysis set and applying the aforementioned 
statistical method. The edoxaban-based regimen will be compared with the VKA­ 
based regimen for superiority only if the non-inferiority of the edoxaban based 
regimen is established first. The edoxaban-based regimerrwill-be considered­ 
superior to the VKA-based regimen, if the upper boundary of the two-sided 95% 
CI for HR falls below 1.00. 
· To evaluate the robustness of the primary analysis, the analysis will be repeated 
using the mITT and PP analysis set. In addition.,the statistical results based on the 
following analysis periods: 'initial dose to final dcise + 30 days', 'overall study 
period + 30 days' will be presented but should be interpreted in a more descriptive 
way. Results for other combinations of analysis sets and analysis periods may be 
presented if considered necessary. 
11.4.2. 
Analysi of the secondary exploratory endpoints 
The main analysis for all secondary exploratory endpoints will be based on first 
occurrence of an (adjudicated) endpoint during the 'overall study period' for all 
subjects belonging to the ITT analysis set and pplying the aforementioned 
statistical method. 
There wiII be no formal statistical testing for secondary exploratory endpoints. 
HRs, CI and p-yalues are provided but should be interpreted in a purely 
descriptive exploratory manner. 
To evaluate the robustness of the main analyses, the analysis will be repeated 
using the mITT and PP analysis set. In addition, the statistical results based on the 
following analysis periods: 'initial dose to final dose+ 30 days', 'overaII study 
period+ 30 days' will be presented but should be interpreted as supportive. 
Results for other combinations of analysis sets and analysis periods may be 
presented if considered necessary. · 
· 
 
11.4.3. 
Pharmacokinetic/Pharmacodynamic Analysis 
11.4.3.1. Pharmacokinetic Analyses 
Not applicable (there will be a separate sub-study protocol) (please refer to section 
17.2). 
 
11.4.3.2. 
Pharmacodynamic Analyses 
Not applicable. 
 
11.4.3.3. Biomarker Analyses 
Not applicable (there will be a separate sub-study protocol) (please refer to section 
17.2). 
 
. 11.4.3.4. Pharmacogenomic Analyses 
Not applicable. 
 
Confidenti l 
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11.4.4. 
Health Economics Outcome Research (HEOR) Analyses 
Not applicable (there will be a separate sub-study protocol) (please refer to section 
17.2). 
 
11.5. 
Safety Analyses 
 
-   - 
11.5.1. 
 Ady_erse ~E YenLAnalfses  
:.  
 ------------- 
Adverse events meeting the criteria defined in Section 9. I will be recorded in the 
eCRF and coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 19.1 or newer. 
Treatment-emergent adverse events (TEAEs) are defined as events which start on or 
after any first dose of the assigned study medication regimen or started prior to but 
then worsened after any first dose of the assigned study medication regimen. An AE. 
that occurs more than 30 days after the date of the last dose of the assigned study 
medication regimen will not be counted as a TEAE. 
The AE analysis will be based on the SAF analysis set. TEAEs will be summarized 
by treatment group. Th!;: incidence of TEAEs will be presented by treatment group, 
by relationship to the assigned study regimen, and by severity. If more than one AE 
is coded to the same preferred term for the same subject, the subject will be counted 
only oncefor that preferred term using the greatest severity and strictest causality for 
the summarization by severity and causal relationship. Frequent TEAE (reported by 
at least 5% resp. 1% of subjects in any treatment group) will be summarized by 
regimen group. 
The incidence of death, SAEs, drug-related SAEs, and AEs leading to permanent 
discontinuation of the assigned study regimen will be summarized. All AEs 
meeting the criteria defined in Section 9.1 will be included in a data listing and a 
listing to display the coding of AEs will be prepared as well. 
11.5.2. 
Clinical Laboratory Evaluation Analyses 
The clinical laboratory evaluations for each scheduled test, including elevated 
liver enzymes and/or bilirubin, and the change from baseline will be summarized 
for the SAF analysis set by treatment regimen. Shift tables (in categories of low, 
normal, and high) will be provided for each treatment regimen for selected 
laboratory parameters. Also, the number and percentage of subjects with clinically 
relevant abnormal laboratory values while on study drug will be calculated for 
each treatment regimen for selected laboratory parameters. All abnormal 
laboratory values will be presented in a listing. 
Details will be outlined in the SAP. 
 
11.5.3. 
Vital Sign Analyses 
Vital signs at each evaluation point and the change from baseline will be 
summarized for the SAF analysis set by treatment regimen. The number and 
percentages of subjects with abnormal vital signs while on study drug will be 
summarized by treatment regimen. 


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11.5.4. 
Electrocardiogram Analyses 
The ECG evaluations at baseline, Month 1, Month 3, Month 6, Month 9, Month 
12 and at FU visit will be summarized by treatmen-t regimen. More details on the 
ECG analysis will be given in the SAP. 
 
11.5.5. 
Physical Examination Analyses 
p ys1ca exammat10n will only be performeo at tnebaselme v1s1t. 
Counts and percentages of physical examination findings will be summarized by 
treatment regimen based on SAF analysis set. 
 
11.6. 
Other Analyses 
Details on the Syntax Score and hospitalisations analyses will be given in the 
SAP. 
 
11.7. 
Interim Analyses 
Not applicable. 
 
11.8. 
Data and Safety Monitoring Board (DSMB) 
There will be an independent DSMB to protect the rights, safety and well-being of 
subjects participating in this study. The DSMB will be involved in the 
· 
management of this clinical study serving as the safety monitoring advisory group 
for the study. The primary role of the DSMB will be to examine the safety data 
(incidence ofMCRB or MEE, or suspected related (S)AEs) on an ongoing basis in 
a unblinded manner to ensure a prompt identification of any safety issues and to 
alert the Executive Committee in case of any clinically concerning safety issues. 
The frequency and extent of the data reviews by the DSMB, details about the 
reviews and stopping rules or criteria for evaluating need for study protocol 
modifications will be described and specifie in theDSMB charter. 
 
11.9. 
Sample Size Determination 
The sample size determination for the study was driven by requirements for 
testing superiority of the edoxaban-based regimen over the VKA-based regimen as 
described above. 
The power calculation was based on a test using the Cox proportional hazards 
model and was performed with PASS version 14.0.4, with the module for two 
survival curves using Cox's proportional hazards model) under the ITT principle 
with a fixed follow-up time of 12 months (i.e., 365 days). 
Based on a review of available safety data, the estimated one-year event rate of the 
primary endpoint (MCRB, i.e. ISTH major or clinically relevant non-major 
bleeding) under the VKA-based antithrombotic regimen is 24%-(13, 27, 28). The 
edoxaban-based antithrombotic regimen is anticipated to reduce the one-year 
incidence to 18% (a relative risk (RR) of 0.75). Under the assumption of an 
exponential distribution, the hazard ratio (HR) equals 0.7231. 
The accrual of 2 x 712 evaluable subjects provides 80% power to demonstrate 
superiority of the edoxaban-based antithrombotic regimen over the VKA-based 


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antithrombotic regimen at a two-sided a=0.05. To compensate for loss-to-follow­ 
up within 12 months, the final sample size is set at 2 x 750 subjects. 
With this sample size, the study has 82% power to show non-inferiority (with a 
margin of 1.20) if the underlying HR is.0.88 at a one-sided significance level of 
2.5%. 
 
 


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12. 
· DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, 
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 Sponsor, site monitors, 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 (as detailed in the 
Monitoring Plan) 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 subject 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. 
TheInvestigator 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 sponsor. Inspection of site facilities 
(e.g., pharmacy, drug storage areas, laboratories, etc.) an. d 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. 
In the event that a regulatory authority informs the Investigator that it intends to 
conduct an inspection, sponsor shall be notified immediately. 
12.2. 
Data Collection 
The eCRF completion should be kept current to enable the monitor to review the 
subject's status throughout the course of the study. .The eCRF is completed by the 
Investigator or qualified designee. Completed eCRFs are r viewed and e-signed 
by the Investigator (or by a sub-Investigator, with permission of the Sponsor). 
 
 
12.3. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of 
subjects or the conduct of the study, sponsor will inform all Investigators involved 
in the clinical study, ethics committees, and regulatory authorities of such 


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information, and when needed, will amend the protocol and/or subject 
information. 
The Investigator should immediately inform the subject orally whenever new 
information becomes available that may be relevant to the subject ' s consent or 
may influence the subject's willingness to continue participation in the study. The 
_ communication should be documented on medical records, for example, and it 
-   -   -   -   - should be-confirmed whether the-subject-is willing-to-re   aini n the study-or-n_ o....-. 
If the subject information is revised, it must be re-approved by EC. The 
investigator should obtain written IC to continue participation with the revised 
written information even if subjects are already informed of the relevant 
information orally. The Investigator or other responsible personnel who provided 
explanations and the·subject should sign and date the revised IC. 
 
 
12.4. 
Data Management 
Each subject will be identified in the database by a unique subject identification 
number as defined by the sponsor. 
To.ensure the quality of clinical data across all subjects and sites, a Clinical Data 
Management review will be performed on subject data according to specifications 
given to the CRO. Data on eCRF is vetted electronically by programmed data 
rules within the application. Queries generated by rules and raised by reviewers 
will be generated within the EDC application. Dui-ing this review, subject data 
will be checked for consistency, omission.s, and any apparent discrepancies. 
Data received from external sources such as centnd labs will be reconciled to the 
clinical database. 
SAEs in the clinical database will be reconciled with the safety database. 
 
 
12.S. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons 
to whom he/she has delegated study duties. -".\,ll persons authorized to make 
entries and/or corre_ctions on eCRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the 
subject's eCRF 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 conespondence. 
The Investigator and study staff are responsible for maintaining a comprehensive 
and centralized filing system (Trial Master File) of all study-related (essential) 
I 
documentation, suitable for inspection at any time by representatives from sponsor 
and/or applicable regulatory authorities. Essential documents include: 
• 
Subject files containing ICs, .and supporting copies of source 
documentation as used for eCRFs completion. In addition, all original 
source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
 
 
 
 
 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 


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• 
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 Sponsor. 
• 
Records related to the study medications delivered 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. 
Essential clinical trial documents (including case report forms) other than subject's 
medical files must be kept for at least 15 years after completion or discontinuation 
of the trial. Subject's medical files should be retained in accordance with applicable 
legislation and in accordance with the maximum period of time permitted by the 
hospital, institution or private practice. It is the responsibility of the sponsor to inform · 
the Investigator/institution as to when the clinical trial documents no longer·need to 
be retained. 
No study document should be destroyed without prior written agreement between 
sponsor and the Investigator. Should the Investigator wish to assign the study 
records to another party or move them to a. nother location, he/she must notify DSE 
in writing of the new responsible person and/or the new location. 
12.6. 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, data correction 
forms, CRFs, inventory of study product, regulatory documents (e.g., protocol and 
amendments, IEC/EC correspondence and approvals, approved and signed ICs, 
Investigator's Agreement, clinical supplies receipts, distribution and return 
records), and oth,er 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 evaluatiqn and reconstruction of the clinical study. These records will be 
· retained1n 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 d be given the opportunity to further store such records. 


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


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14. 
PUBLICATION POLICY 
. 
. 
A study site may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until one year after the study has 
ended, whichever occurs first. Therefore, the study site will have the opportunity 
to publish the results of the study, provided that sponsor and the executive 
committee has had the opportunity to review.and comment on the study site's 
-·  _-  -•p roposed-publication-pi-ior-to-its  being-submitte0-fm --pu0      lication-with-the-advice--01c ---------------------------- ­ 
company patent council and in accord with needs for subject protection. 


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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 
_m-otocol. A subs tantial.p rotocol amendment may be implemented after it has been 
approved by the IEC, unless immediate implementationof the change is necessary 
for subject safety. In this case, the situation must be documented and reported to 
the IEC within five working days. The sponsor will assure the timely submission 
of substantial amendments to regulatory authorities. 
 
15.2. 
Address List 
 
15.2.1. 
Sponsor 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48 
81379 Munich, Germany 
 
15.2.1.1. 
DSE Project Leader 
 
15.2.1.2. 
DSE Medical Expert 
15.2.2. 
Academic Research Organizations 
European Cardiovascular Research Institute (ECRI) 
PO Box 2125, 3000 CC Rotterdam, The Netherlands. 
 
 
Kompetcnznctz Vorhofflimmern e.V. (AFNET e.V.) 
Mendelstr. 11, D-48149 Mtinster, Germany. 
 
 
 
Cardialysis 
Westblaak 98, 3012 KM Rotterdam, The Netherlands. 


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15.2.3. 
CRO 
Chiltern International 
37 bis rue de Villiers, 
92200 Neuilly sur Seine, 
France 
 
15.2.3.1. CRO Medical Monitor 
Canada Square Office House, Ganz u. 12-14, 4, Budapest, Hungary, H-1027 
 
 
 
15.2.3.2. CRO Project Manager 
 
 
 
15.2.4. 
Drug Safety 
 
15.2.4.1. 
DSE 
15.2.4.2. 
CRO 
 
171 Bath Road, Slough, 
Berkshire, SLl 4AA, United Kingdom 
 
 
15.2.5. 
Interactive Web Voice Response System (IXRS) 
Endpoint Clinica l, Inc. 
55 Francisco Street, Suite 200 
San Francisco, CA 94133 


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o 
. .. 
 
 
 
15.2.6. 
Bioanalytical Laboratory 
Europe (except Ukraine) 
Medical Laboratory SYNEVO 
Marynarki Polskiej Str.163 
(in building C200 office) 
Gdansk, POLAND 
80-868 
 
 
 
 
 
Ukraine 
Synevo Central Lab Ukraine 
46/2 building 3 
Akademik Palladin Avenue 
03680 K iv Ukraine 
 
 
 
 
 
 
Korea/Taiwan 
GCRL (Green Cross Reference Lab) 
314 Bojung-d ng, Giheung-gu, 
Y  .'- K 
-- d K ea 


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16. 
REFERENCES 
1. Lip GY, Windecker S, Huber K, Kirchhof P, Ma in F, Ten Berg JM, et al. 
Management of antithrombotic therapy in atrial fibrillation patients presenting with 
acute coronary syndrome and/or undergoing percutaneous coronary or valve 
interventions: a joint consensus document of the European Society- of Cardiology 
Working Group on Thrombosis, European Heart Rhythm Association (EHRA), 
             - -   - European-Association-of--J>erc  utaneous-GarEli0vase    ular_.: I nter-ventions   - (E AP8-I)-anr1  -------- ­ 
 
European Association of Acute Cardiac Care (ACCA) endorsed by the Heart 
Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart 
J. 2014;35(45):3155-79. 
. 
2. Lopes RD, Pieper KS, Horton JR, Al-Khatib SM, Newby LK, Mehta RH, et al. 
· Short- and long-term outcomes following atrial fibrillation in patients with acute 
coronary syndromes with or without ST-segment elevation. Heart (British Cardiac 
Society). 2008;94(7):867-73. 
3. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al. 
Updated European Heart Rhythm Association Practical Guide on the use of non­ 
vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. 
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of 
the working .groups on cardiac pacing, arrhythmias, and cardiac cellular 
electrophysiology of the European Society of Cardiology. 2015;17(10):1467-507. 
4. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al. 2014· 
ESC/EACTS Guidelines on myocardial revascularization: The Task Force sin 
Myocardial Revascularization of the European Society of Cardiology (ESC) and the 
European Association for Cardio-Thoracic Surgery {EACTS)Developed with the 
special contribution of the European Association of Percutal).eous Cardiovascular 
Interventions (EAPCI). Eur Heart J. 2014;35(37):2541-619. 
5. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 
ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of 
the American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines and the Society for Cardiovascular Angiography and 
Interventions. Journal of the American College of Cardiology. 2011;58(24):e44-122. 
6. Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, et al. 
Management of patients with atrial fibrillation (compilation of . 2006 
ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations):. a report of the 
American College of Carqiology/American Heart Association Task Force on 
Practice Guidelines. Journal of the American College of Cardiology. 
2013;61(18):1935-44. 
7. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 
2012 focused update of the ESC Guidelines for the management of atrial fibrillation: 
an update of the 2010 ESC Guidelines for the management of atrial fibrillation. 
Developed with the special contribution of the European Heart Rhythm Association. 
Eur Heart J. 2012;33(21):2719-47. 
8. Faxon DP, Eikelboom JW, Berger PB, Holmes DR, Bhatt DL, Moliterno DJ, et 
al. Consensus document: antithrombotic therapy in patients with atrial fibrillation 
undergoing coronary stenting. A North-American perspective. Thrombosis and 
haemostasis. 2011;106(4):572-84. 
9. Moser M, Olivier CB, Bode C. Triple antithrombotic therapy in cardiac patients: 
more questions than answers. Eur Heart.J. 2014;35(4):216-23. 


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10. You JJ, Singer DE, Howard PA, Lane DA, Eckman· MH, Fang MC, et al. 
Antithrombotic therapy for atria·l fibrillation: Antithrombotic Therapy and 
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence­ 
Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e531S-75S. 
11. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et 
al. 2014 AHA/ACC/HRS guidelin for the management of patients with atrial 
fibrillation: ex cutive summary: a · report of the American College of 
-        c araio logy7American Heart Association Tasi<Force on practice guide-1-·in-e-s -and_ the  
 
Heart Rhythm Society. Circulation. 2014;130(23):2071-104. 
12. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, et 
al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant 
therapy and undergoing percutaneous coronary intervention: an .open-label, 
randomised, controlled trial. Lancet (London, England). 2013;381(9872):1107-15. 
13. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et 
al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 
2013;369(22):2093-104. · 
14. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. 
Standardized bleeding definitions for cardiovascular clinical trials: a consensus 
report from the Bleeding Academic Research Consortium. Circulation. 
2011;123(23):2736-47. 
15. Schulman S, Kearon C. Definition ofmajor bleeding in clinical investigations of 
antihemostatic medicinal products· in non-surgical patients. J Thromb Haerriost. 
2005;3(4):692-4. 
16. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of 
A. Definition of clinically relevant non-major bleeding in studies of anticoagulants 
in atrial fibrillation and venous thromboembolic disease in non-surgical patients: 
communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119- 
26. 
17. Edoxaban IB, version 15.0, 12 JUN 2015. 
18. Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, 
et al. Edoxaban versus warfarin for the treatment of symptomatic venous 
thromboembolism. N Engl J Med. 2013;369(15):1406-15. 
19. Investigators AWGotA, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, et 
al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the 
Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events 
(ACTIVE W): a randomised controlled trial. Lancet (London, England). 
2006;367(9526):1903-12. 
20. Bhatt DL, Cryer BL, Con:tant CF, Cohen M, Lanas A, Schnitzer TJ, et al. 
Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 
2010;363(20):1909-17. 
21. Wiviott SD, Braunwalci E, McCabe CH, Mo talescot G, Ruzyllo W, Gottlieb S, 
et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl 
J Med. 2007;357(20):2001-15. 
. 
22. Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, et al. 
Hemorrhagic events during therapy with recombinant tissue-type .plasminogen 
activator, heparin, and aspirin for acute myocardial infarction. Results of the 
Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med. 
1991;115(4):256-65. 


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23. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al.· 
Clinical end points in coronary stent trials: a case for standardized definitions. 
Circulation. 2007;115(17):2344-51. 
24. Thygesen K, Alpert JS,.Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. 
Third universal definition of myocardial infarction. Eur Heart J. 20I2;33(20):2551- 
67. 
. . 
25. Moussa ID, Klein LW, Shah B, Mehran R, Mack MJ, Brilakis ES, et al. 
- - - - Consiaeration of a new definition of clinically relevant myocardial infarction after 
coronary  revascularization: an. expert  consensus  document  from  the Society for 
Cardiovascula·r Angiography and Interventions (SCAI). Journal of the American 
College of Cardiology. 2013;62(17):1563-70. 
26. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine 
the optimal intensity of oral anticoagulant therapy. Thrombosis and haemostasis. . 
1993;69(3):236-9. 
27. Daiichi Sankyo, ENGAGE clinical study report, 2013. 
28. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, 
et al. Risk of bleeding withsingle, dual, or triple therapy with warfarin, aspirin, and 
clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170(16):1433- 
41. 
29. Lip GY,·Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk 
stratification for predicting stroke a_nd thromboembolism in atrial fibrillation using a 
novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 
2010;137(2):263-72. 
30. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. 
Validation of risk stratification schemes for predicting stroke and thromboembolism 
in patients with atrial fibrillation: nationwide cohort study. BMJ.2011;342:dl24. 
31. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user­ 
friendly score (HAS-BLED) to assess I-year risk of major bleeding in patients with 
atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-100. 
32. Lane DA, Lip GY. Use of the CHA(2)DS(2)-VASc and HAS-BLED scores to 
aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. 
Circulation. 2012;126(7):860-5. 
33. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron. 1976;16(1):31-41. 
34. Bonita R, Beaglehole R. Recovery of motor function after stroke. Stroke. 
1988;19(12):1497-500. 
35. Rankin J. Cerebral vascular accidents in patients over the age of 60. IL Prognosis. 
Scott Med J. l 957;2(5):200-15. 
36. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. 
Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 
. 1988;19(5):604-7. 
37. Jung BC, Kim NH, Nam GB, Park HW, On YK, Lee YS, et al. The Korean Heart 
Rhythm Society's 2014 Statement on Antithrombotic Therapy for Patients with 
Nonvalvular Atrial Fibrillation: Korean Heart Rhythm Society. Korean Circulation 
Journal. 2015;45(1):9-19. 
38. Serrano Jr. CV, Fenelon G, Soeiro AM, Nicolau JC, Piegas LS, Montenegro ST, 
et al. Brazilian Society of Cardiology. Brazilian Guidelines on Antiplatelet and 
Antfooagulant Agents in Cardiology. Arq Bras Cardiol. 2013;101(3Supl.3):1-93. 
39. Levey, AS, Stevens LA, Schmid CH, Uhang YL, Castro AF, Feldman HI, Kusek 
JW, Eggers P, Van Lente F, Greene T, Coresh J for the CKD-EPI Chronic Kidney 


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Disease Epidemiology Collaboration): A New Equation to estimate Glomerular 
Filtzration Rate. Annuals oflntemal Medicine; volume 150, Numer 9: 607-612 
 
 
 
 
 
 


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17. 
APPENDICES 
 
17.1. 
Study Organization 
 
17.1.1. 
Data and Safety Monitoring Board (DSMB) 
There will be an independent DSMB to protect the rights, safety and well-being of 
- - 
 s-u-'-bjects partici12ating in the  stud  . The DSMB consists of   ualified scientists  who 
are not Investigators in the study and not otherwise directly associated with the 
sponsor, and has the primary role in examining the safety data and other pertinent · 
data. The DSMB monitors study data in an un-blinded, ongoing manner and alerts 
the Executive Committee in case of any clinically concerning safety issues. 
The frequency and extent of the data reviews by the DSMB, details about the 
reviews and stopping rules or criteria for evaluating need for study protocol 
modifications will be desc;ribed and specified in the DSMB charter. The DSMB 
can recommend modification of the study protocol, or study, or treatment regimen 
to the Executive Committee based on pre-specified rules described in the DSMB 
ch rter. 
 
All activities of the DSMB will be documented. This documentation will include 
data summaries and analyses (see Section 11.8) provided to the DSMB as well as 
minutes of the meetings. The documentation will remain confidentia·l within the 
DSMB until the study is completed. An independent statistician who is not 
otherwise involved in the study will prepare the required data outputs and provide 
the outputs to the DSMB as per the DSMB charter. 
 
 
17.1.2. 
Clinical Events Committee (CEC) 
An independent CEC reviews and adjudicates the following events in a blinded 
manner and without any knowledge of the subject's assigned treatment regimen: 
Clinically relevant non-major bleeding; 
- 
Major bleeding; 
- 
Minor bleeding; 
- 
Death from any cause; 
- 
Suspected stroke; 
Suspected SEE;• 
Suspected MI; 
- 
Suspected stent thrombosis; 
Details about the definitions of the endpoints (Section 7.3), endpoint sub­ 
categories and other CEC processes are described in the CEC charter. 
 
The single components of the composite primary (and secondary endpoints 
mentioned above are explored, as well as specific subcategories (e.g., ICH, 


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ischernic stroke) and event classifications according to other definitions (e.g., 
BARC, TIMI). 
 
17.1.3. 
Executive Committee 
The Executive Committee will be responsible for the overall design, conduct, and 
supervision of the study, including the development of any protocol amendments. 
The Executive C_o mmittee_will also_r_eview  _the progress of.the~st udy_a Lfegula 1· ------------------------------------------ ­ 
intervals to ensure subject safety and study integrity. The Executive Committee 
will be comprised of designated representatives from the Academic Research 
Organizations (AROs), CRO, and Sponsor. 
17.1.4. 
Steering Committee 
A stQdy Steering Committee will include the Executive Committee members and 
Natio,nal Lead Inv.estigatorsand will be responsible for supporting the Executive 
Committee in making strategic decisions for the study, working with the 
Executive Committee to provide overall oversight for the trial, and enhancing the 
study implementation to optimize the quality of the data and study integrity. 
 
17.1.5. 
Operations Committee 
The Operations Committee will be responsible for the ongoing monitoring of the 
study data and implementation of steps to improve the quality of the study 
conduct. The Operational Committee will be comprised of designated 
representatives of CROs and Sponsor and will report at regular intervals to the 
Executive Comm_ittee 
on the·progressof the study. 
 
 
17.2. 
Substudies 
Subjects in this study may participate in one or more substudies. Dedicated sites 
are invited for participation according to sites capabilities to meet specific 
substudies requirements and on the required·  number of observations. Currently, 
substudies are being considered involving blood sample collection for bio marker 
substudy (VASP protein, anti-FXa activity, whole blood clotting time (WBCT), 
Health Economics Outcome Research (HEOR) and possible exploratory 
biomarkers. The HEOR substudy may include patient reported outcome measures 
(PROM), healthcare resource utilization measures and other measurements of the 
clinical effectiveness of the study regimens. 
The substudy-specific requirements and procedures will be provided as a separate 
protocol of this main study. Results for the substudies will be reported 
subsequently to those of the main study.by a separate report. Any sub-study 
protocol will be subject of separate approval by Regulatory Authorities and 
· IRBs/IECs. 


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17.3. 
ISTH Bleeding Criteria 
 
 
Table 17.l : ISTH Bleedine Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please refer to Section 7.3 for other details on endpoint definitions. 
ISTH Bleeding Criteria (15, 16) 
Major bleeding 
• 
Clinically ove11 bleeding that is associated with: 
o -A fall m hemoglobin of 2 glc!C-{l-:24 mmol/I;) or more, or 
o 
A transfusion of 2 or more units of whole blood or packed red blood 
cells, or 
· 
· 
o 
Symptomatic bleeding in a critical site or organ such as: intracranial, 
intraspinal, intraocular, retroperitoneal, pericardia!; intra-articular, 
intramuscular with compartment syndrome,, or 
· 
o 
A fatal outcome 
Clinically relevant non-major (CRNM) bleeding 
• 
Any sign or symptom of hemorrhage (e.g., more bleeding than would be expected 
for a clinical circumstance, including bleeding found by imaging alone) that does 
not fit the criteria for the ISTH definition of major bleeding but does meet at least 
on of the following criteria: 
o 
requiring medical intervention by a heal.thcare professional 
o 
leading to hospitalization or increased level of care 
o 
prompting a face to face (i.e., not just a telephone or electronic 
communication) evaluation. 
Minor 
• 
Bleeding episodes not requiring any medical attention and therefore not meeting the 
criteria for major or clinically relevant non-major bleeding. 


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17.4. 
Definition of terms 
Abnormal liver function is defined as chronic hepatic disease (e.g., cirrhosis) or 
biochemical evidence of significant hepatic der ngement (e.g., bilirubin > 2 
times the ULN, in association with aspartate aminotransferase/alanine 
transferase/alkaline phosphatase> 3 times the upper limit of normal, and so 
forth). 
Abnormal renal function is defined as chronic dialysis, renal transplantation, or 
serum creatinine 
200 µmol/L ( 2.26 mg/dL). 
Congestive heart failure is defined as the current presence or prior history of 
clinical congestive heart requiring medical attention and medical therapy or 
documented Ejection Fraction :S35% (left ventricular systolic dysfunction). 
Diabetes Mellitus includes diabetes requiring treatment with diet only or with 
pharmacologic therapy (insulin, oral hypoglycemic agents). 
Documented clinical need is defined as a known record in any form (incl. 
written, electronic or verbal) recording pertinent subject data with regard to the 
clinical reason for the choice of an alternative medication. This reason must be 
captured and pre-declared before subject randomization. 
Labile INRs is defined as unstable or high INRs or poqr time in therapeutic 
rarige (e.g. , <60%) while on a vitamin K antagonist. 
Hypertension is defined as hypertension requiring pharmacologic therapy to 
maintain a BP< 140/85 mmHg or untreated hypertension documented by BP> 
140 mmHg systolic or> 90 mmHg diastolic on two separate occasions. 
Stroke: Stroke is defined as an abrupt onset, over minutes to hours, of a focal 
. neurological deficit that is generally in the distribution of a single brain artery 
(including the.retinal artery) and that is not due to an identifiable non-vascular 
cause (i.e., brain tumor or trauma). The deficit must either be associated with 
symptoms lasting more than 24 hours oi: result in death within 24 hours of 
symptom onset. 
TIA: TIA is defined as an abrupt onset, over minutes to hours, ofa focal non- 
fatal, neurological deficit in the distribution of a single brain artery (including 
the retinal artery) that lasts less than 24 hours and that does not satisfy the 
definition of stroke above. 


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17.5. 
Components of the CHA2DS2-VASc Score and HAS-BLED Score 
 
Ta ble 17.2.· Co m11one   nts of the CHA -, DS-,-VASc Score 
 
 
 
CHA2DS2-VASc (29, 30) 
Score 
Congestive heart failure 
1 
Hypertension 
1 
Age 
75 years 
2 
Diabetes mellitus 
I 
Stroke/TIA/TE 
2 
Vascular disease (prior MI, PAD, or aortic plaque) 
1 
Aged 65 to 74 years 
I 
Sex category (i.e., female sex) 
1 
Maximum score 
10 
Abbreviations:MI: myocardial infarction; PAD: peripheral artery disease; TIA: transient ischemic 
attack; TE: thrombo-emboli$m. 


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Table 17.3.· Comoonents of the HAS-BLED Score 
 
 
 
 
 
 
 
 
 
Abbreviations: Cr: serum creatinine; ULN: upper limit of normal; AST: aspartate 
aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; INR: international 
normalized ratio; NSAIDs: non-steroidal anti-inflammatory drugs; TTR = time in therapeutic 
range; ULN = upper limit of normal. 
HAS-BLED (31, 32) 
Score 
Hypertension History (systolic blood pressure 
> 160 mmHg systolic) 
I 
Abnormal Renal Function (Dialysis, transplant, Cr 
> 2.6 mgldL or> 200 JJmoILL) 
I 
Abnormal Liver Function (Cirrhosis or Bilirubin 
>2x ULN with AST/ALT/ALP >3x ULN) 
l 
Previous History of Stroke 
1 
Prior Major Bleeding or Predisposition to Bleeding 
(e.g., anemia) 
1 
Labile lNRs (Unstable/high INRs, TTR < 60%) 
1 
Elderly (Age> 65 years) 
I 
Drug Usage (i.e., Antiplatelet agents, NSAIDs) 
I 
Excessive Alcohol Use ( 2': 8 drinks/week) 
I 
Maximum score 
9 


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17.6.  
Estimation of Creatinine Clearance (CrCL) and CKD-EPI 
Equation for Estimating GFR on the natural Scale 
 
 
Creatinine Clearance Using Cockcroft-Gault Formula (33) 
The Cockcroft-Gault formula for the calculation of CrCL will be used in this study. 
- 
Greatinine-Glearance-for-Males.   
 
CrCL = [140 - age (years)] x [body weight (kg)] / [72 x serum creatinine 
(mg/dL)] 
 
Creatinine Clearance for Females: 
CrCL = 0.85 x [140 - age (years)] x (body weight (kg)] I [72 x serum creatinine 
(mg/dL)] 
. 
The Chronic Kidney Disease Epidemiology Equation (CKD-EPI) to estimate 
the glomerular filtration rate (GFR) 
 
The table is taken out of the manuscript, published in Annals of Internal 
medicine 2009 (39) 
 
 
r.,b/t> .! .  The CICO-EPI Equ uon for Est1m;i1tng GFR on the 
N.atural Scale" 
R.iu •nd Su 
 MNm 
C,uUnlno 
lrf,fl 
i•mol/L 
lmt/dl.J 
 
-.62(-0071  GfR • 166 
r/OJ) aw.·• t0.993)­ 
2(:,.07·)     GFR  •   166   •· (ScrltD )  1 "" 
l'0.993)'''" 
:. S0 (,;0 9)     GFR -  16,1      (Su /0 9) 0   "'         •   (0993)''" 
;,.SO,,I   0.9l     GfR -   •63  •  <Sal0-9)   "=- . f0.99  3)"' " 
Whlle or o 
. 
F 
67 /.::07J  GfR •  t .:.i   (Sa/07)   n• . (0993),_ 
> 61 (>0 1)    GfR -   l.:.l < (Scr/0 ')   1 ""'  •' (099'3)"" 
Mu 
--:SO (-c09l     GrR •  1, 
·  cScr/0.9] 
"'     ,  (0.993)""" 
:-80 -(:  0 9)     GFR -   IOI    ·   !xJ/09)  ,,.,.. • <0993/AI• 
U:U,U'I - l hron,c h:.,dn<! IJ...,..., I ridcm.,I,. ( oil,..._,,,,.,.., Lrll. • ,;J,.'­ 
rnt"n.d.u hl1r.mon n:rt.. 
• r,r1""'-iiC\.I fill 'f--«dt1hJ  f.h.•(   .n   ,m.,I  \l(fUfn 1.tr 'm oil\(    l  H, I  To u,O\c-n \JS:R 
from mlJnun pn  l.i...\ m:  m  nilJ,  '    -1.   i m·  .. mu1urh·· br O.ou;-. \\'c Jcn"N 
tqu:.1uc,n coclth. u Iron, pr-..·ltd <l:C'i rlornxm 
1r.J-.•rml ,.t!..JJorm Wu , 
fh<  t:!:U.f.PJ  hf.UHM,·•Clr(t,.1<-.J  ,u:  .a   l10     •r  , r.uuon. 
(;J:-R - MI 
min!   rl><,  IY'  • m_,.(<,,,1,.. 11  '·'" / O?'!\ · I !118 (,lfrnul<I •  1 15'1 (,( 
hl:it..1)1    ¥1-b.ttr 
u  wrum Jt'J.ntun.c:. ,-: i101fo,fun.,Jc,:, lnJ   OD for  rt:.:4a tt   u 
-o.J!-J furfirtm.i.il"'l.tnd - 0.1 I l for m.:.la.., min Ltut,0.!.M 1M mininwm of XJ° f ,c.or 
.I .nJ mn n·,,,h-..itn th nu11mum ti Xi' K 1., I ln du, uM.,. 1h,:1r.11l ipl-.. 1ir.,n 
J41 o n fot t4t .ind • :arr 11'\.:orponuJ ;n11, th< inc.c-n;-qic. llll1Kh rc,11lt, ,n dtJ­ 
fHnU 1ritrh<;1t fett .11,,. .,mJ k"I <otnhHUlu>m 


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17.7. 
Modified Rankin Scale. 
 
 
Table 17.4:Modified Rankin Scale 
 
 
 
 
17.8. 
·  Regional Guideline Recommendation.sfor INR. 
 
 
Table 17.5: Regional Guideline Recommendations for INR 
 
                                
Guideline 
Ref. 
Target INR Range 
Start VKA at INR 
Europe 
(1) 
2.0 - 3.0 
Korea 
(37) 
2.0 - 3.0 
<2.5 
< 2.5 
Taiwan 
Brazil 
n Pending publication. 
# 
 
(38) 
· 2.0-3.0 
2.0-3.0 
< 2.5 
<2.5 
Score(34-36) 
Description 
0 
No symptoms at all 
I 
No signi fica_nt disab ility despite symptoms; abl·e to carry out all 
usualauhes ana achv1t1es 
2 
Slight disability; unable to carry out all previous activities, but able 
to look after own affairs without assistance 
3 
Moderate disability; requiring some help, but able to walk without 
assistance 
4 
Moderately severe disability; unable to walk without assistance and 
unable to attend to own bodily needs without assistance 
5 
Severe disability; bedridden, incontinent, and requiring constant 
nursing care and attention 
6 
Dead 


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17.9. 
Schedule of Events 
Ta ble 17.6·Sched ule of Eve nts 
Visit number 
1 
2 
3 
4 
s 
6 
7 
8 
9 I IO 
11 
12 
13 
14 
Period 
Screening 
Planned tr eat ment I 
Post- 
trentm 
ent 
Visit 
Pre- 
screening 
Baseline / 
randomization 
(DAY 1) 
Discharge 
V 
TA 
V 
TA TA 
V 
TA TA 
V 
TA TA EO 
T 
Follow 
-up 
Visit timing 
4 h - 5 d post-PCI 
I M 
2M 
3M 
4M 
SM 
6M 
7M 
S M 9M 
I 
IOM llM 
12 
M 
JM 
post- 
E0TP 
W indow (days) • 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 I±7 
±7 
±7. 
±7 
+7 
Inclusion/Exclusion Criteria 
X 
X 
Check INR S 2.5 (local lab results) vs. exclusion 
criteria bc. 
X 
Demographic information 
X 
I 
Study informed·consentd 
X 
Contact lXRS for pre-declaration• and 
randomizationr 
X 
Administer OAC and antiplatelet medications s 
X 
X 
Dispense assigned OAC and antiplatelet 
medicationsh 
X 
X 
X 
X 
X 
Prior medications within 30 days of randomization 
X 
I 
Medical history (including bleeding history) 
X 
Local lab results; 
X 
X 
(INR 
011/y) 
X 
(INR 
011/y) 
X 
(INR 
011/y) 
X 
(INR 
011/y) 
X 
(INR 
011/y) 
Physical exami nation 
X 
I 
Vital signs i 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 


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Version 3.0, 28 February 2017 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Irn 
I I 
12 
13 
14 
Per iod 
Screening 
Planned treatment 
I 
Post- 
tre:itm 
ent 
Visit 
Pre- · 
scree ning 
Baseline/ 
randomi zatio n 
(DAY 1) 
Discharge 
V 
TA 
V 
TA TA 
V 
TA TA 
V 
I 
TA TA EO 
T 
Follow 
-up 
Visit timing 
4 h- 5 d post-PC! 
IM 2M 
3M 
4M 
S M 6M 
7M 
SM 
M 
I 
IOM llM 12 
M P 
I M 
p ost- 
EOTq 
Window· (days) • 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
1±7 
±7 
±7 
±7 
+7 
Index-PC! cqronary angiogramsk 
X 
Concomitant medication 
X 
X 
X 
X 
Ix 
X 
X 
Blood draw for central safety lab 1 
X 
X 
X 
X 
X 
X 
Urine sampling (pregnancy testing) for women 
with childbearing potential only 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ix 
X 
X 
X 
Review study regimen compliance & interruptions 
m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xI 
X 
X 
X 
AE I events reporting " 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Obtain INR and VKA dose information monthly 
(VKA subjects only)0 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ix 
X 
X 
X 
I 
Abbreviations: AE = adverse event; ALT= alanine transaminase; AST= aspartate transaminase; ALP= alkaline phosphatase; CrCL = creatinine clearance; estimated glomerular 
filtration rate (GFR) M = month; ECG = electrocardiogram; eCRF = electronic case report form; EOT = end- of- treatment; h = hours; ID = identification; INR = international 
normalized ratio; IXRS = Interactive WebNoice Response System; LD = last dose; OAC = oral anticoagulant; P C I = percutaneous coronary interver tion; TA= Te lephone 
assessment; TBL = total bilirubin; VKA = Vitamin K antagonist; V = On-site visit; WBC = white blood cell. 
• Visit/assessments windows are provided as a guide, but visits should be scheduled taking into account the need to dispense study medications. 
b    INR must be 5 2.5 at screening. 
I 


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Versiob 3.0, 28 February 2017 
 
° Check the most recent results from local laboratory tests done post-index PCI against the exclusion criteria (estimated CrCL, hemoglobin, platelet count and WBC with 
differential if elevated). CrCL should be calculated by the Cockcroft-Gault formula as described in Appendix 17.6. 
d S ubjects eligible to participate in the study provide Written IC before randomization or any study-specific procedures. Once written IC is obtained, subject should be randomized 
without delay. 
0 Pre-declaration of duration of ASA treatment if randomized to VKA and of P2Y12 antagonist other than clopidogrel, if applicable. 
r For subjects randomized to edoxaban: If subject is on: (a) VKA, the first dose ofedoxaban can be started when INR :S 2.5. (b) NOAC, discontinue  OAC and start edoxaban at 
the time of the next scheduled NOAC dose. 
Continue clopidogrel bisulfate 75 mg once-daily (or other P2Y12 antagonist) with medication as provided by IXRS and discontinue ASA, if being taken. 
For subjects randomized to VKA: If subject is on: (a) VKA, continue with medication as provided by IXRS when INR :S2.5. (b) NOAC, discontinue the NOAC and start VKA 
at the time of the next scheduled NOAC dose. 
· 
Continue clopidogrel bisulfate 75 mg once-daily (or other P2Y12 antagonist) with. medication as provided by lXRS. 
Start or continue ASA (100 mg once-daily), guided by the clinical presentation (ACS or stable coronary disease) and upon the CHA2DS 2- VASc and HAS-BLED score and pre- 
declare use and treatment duration. 
· 
i;.h Sponsor supplies study subjects with edoxaban, VKA, P2Y12 antagonist and ASA (if applicable) according to assigned regimen at randomization. Medication kits are assigned 
through the IXRS. Accountability for medications provided by DS is performed at dispensing visits and the EOT visit. 
Check the most recent results from local laboratory tests done Cardiac enzymes before and after index PCI (closest to post-index PCI and most recent prior to randomization, 
respectively); Hemoglobin, platelet count, WBC (with differential if elevated), total bilirubin (if elevated, determine conjugated/unconjugated bilirubin fraction) done post-index 
PCI; Total cholesterol and triglycerides done the closest to the index-PC! procedure. 
At each on-site visit, check the CrCL as estimated by the Cockcroft-Gault formula. 
j Vital signs include sitting blood pressure, weight and height. Height only needs to be recorded at screening. 
k    In index angiograms both the right coronary artery (RCA) and left coronary artery (LCA, incl. LAD and LCX) must be imaged.. 
. 
1 Blood draw for central laboratory analysis including safety lab (lNR, liver:function, serum chemistry, hematology) as described in section 9.6. At each visit individual blood 
samples are collected; stored and shipped according to the Laboratory-Ma nual. 
m Antithrombotic regimen compliance is achieved by assessing subject compliance at each visit/ telephone assessment (both by pill count, self-reporting/ physician-reporting and 
by INR values for VKA subjects only). ln case of a suspected study endpoint, an additional assessment for subject compliance to the assigned regimen must be performed. 
"AEs, endpoint events, and events of special interest should be reported as soon as site personnel learn of the event. Endpoint event and AE reportingjsho uld occur throughout the 
study and not be restricted to specific visits. If ALT or ALT>3xUNL with simultaneous TBL> 2xUNL is observed, then ALP should be determined. 
Report ongoing all endpoints and all AEs including abnormal laboratory findings. Any laboratory measurements performed during unscheduled visits are collected. 
0 VKA subjects only; INR values and VKA dose are collected monthly and entered into the  eCRF either  during the on-site visits by local laboratory  determination  or  during the 
subject's telephone assessments. INR values and VKA doses collected through the general practitioner or local anticoagulation clinic must also be pc    nsidered 
and collected but 
this does not constitute a waiver for subjects planned TA or lNR determination during on-site visits. 
P    Subjects are transi ioned_to an available marketed OAC of t_he Invest!g tor'   choice. Th   Io estigator wi l_follow the transition strategy in_ the ap:p ol ved 
product label. Subjects 
who prematurely d1scontmue study OAC are requested to contmue chmcal follow-up w.1th either study v1s1ts or telephone contacts accordmg to this schedule. 


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q All randomized subjects who are on study medication (study edoxaban or VKA) at 365 days, wiJI have a post-treatment contact at 30-37 days after the EQT visit to collect data 
on concomitant medications, SAEs, and other safe  events of interest. 
I