Clinical trial NCT02943785
Conditions: Atrial Fibrillation
Keywords: Transcatheter Aortic Valve Implantation -- TAVI Anticoagulation Atrial Fibrillation ENVISAGE-TAVI-AF
Sponsor: Daiichi Sankyo
Start date: 2017-03-21; Completion date: 2021-02-28
Enrollment: 1426 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
When the upper chambers of a person's heart receive or generate irregular electrical signals, it causes abnormal rhythm in the heartbeat. This is called atrial fibrillation.

Atrial fibrillation goes along with blood clots that may cause mainly strokes and less often other diseases, such as a heart attack. Some patients with atrial fibrillation have other heart disease, such as heart valves that may need to be replaced using catheters.

Often doctors give patients drugs that reduce those blood clots. These are either vitamin K antagonist (VKA) or direct anticoagulants, such as edoxaban. In these patients, it is unclear which of the drugs is better for reducing stroke without increasing severe bleedings.

Detailed description:
Use of Edoxaban in patients with atrial fibrillation (AF) and indication to chronic oral anticoagulation (OAC) after transcatheter aortic valve implantation (TAVI)

Objective:

* To assess the effect of Edoxaban versus vitamin K antagonist (VKA) on net adverse clinical events (NACE), i.e., the composite of all-cause death, myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SEE), valve thrombosis, and major bleeding (International Society on Thrombosis and Haemostasis \[ISTH\] definition).
* To assess the effect of Edoxaban versus VKA on major bleeding (ISTH definition).

Arms: arm 1: Edoxaban-based regimen 60 mg and 30 mg film coated tablet for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing must follow the locally approved label. arm 2: VKA-based regimen oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator will monitor the patient and adjust the VKA dose to maintain the dose within target.
Interventions: intervention 1: Edoxaban-based Regimen intervention 2: VKA-based Regimen
Intervention descriptions: intervention 1: 15 mg, 30 mg and 60 mg film coated tablet for oral use (with anti-platelet therapy pre-declared at randomization if prescribed) intervention 2: Dosed at International Normalized Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in the country location (with anti-platelet therapy pre-declared at randomization if prescribed).

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
EDOXABAN VERSUS STANDARD OF CARE AND 
THEIR EFFECTS ON CLINICAL OUTCOMES IN 
PATIENTS HAVING UNDERGONE 
TRANSCATHETER AORTIC VALVE 
IMPLANTATION – IN ATRIAL FIBRILLATION 
EDOXABAN (DU-176B-C-U4001) 
ENVISAGE-TAVI AF 
EudraCT NUMBER 2016-003930-26/IND NUMBER 77 254 
Sponsor's Protocol Code Number DU-176B-C-U4001 
VERSION 4.0 29 JUL 2019 
DAIICHI SANKYO 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document prepared by DAIICHI SANKYO Inc. Global 
Medical Affairs is proprietary to Daiichi Sankyo. The information is provided to you in 
confidence which is requested under an agreed upon and signed Confidentiality and 
Disclosure Agreement. Do not give this document or any copy of it or reveal any 
proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized 
representative of Daiichi Sankyo. 




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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
 
 
INVESTIGATOR’S SIGNATURE 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorization from the Sponsor. It is, 
however, permissible to provide information to a 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 considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Conference on 
Harmonisation Guidelines on Good Clinical Practice (International Committee on 
Harmonisation [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. 
 
 
 
Print Name 
Signature 
 
 
Title 
Date (DD MMM YYYY) 


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Protocol DU176B-C-U4001 
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CRITICAL STUDY CONTACTS LIST 
 
Sponsor (United States): 
Daiichi Sankyo Inca 
211 Mt Airy Rd 
Basking Ridge, NJ 07920 
United States 
Legal Representative 
(Europe) 
Daiichi Sankyo Europe GmbH 
Zielstattstr. 48 
81379 Munich 
Germany 
Legal Representative 
(Japan) 
Daiichi Sankyo Company Limitedb 
3-5-1, Nihonbashi Honcho 
Chuo-ku 
Tokyo 103-8426 
Japan 
Contract Research 
Organization: 
Covance Inc 
210 Carnegie Center Drive, 
Princeton NJ 08540 
United States 
a. 
a: Daiichi Sankyo Pharma Development is an unincorporated division of Daiichi 
Sankyo Inc. 
b. b: Daiichi Sankyo Company Limited is the holding company of Daiichi Sankyo, Inc. 


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PROTOCOL SYNOPSIS 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
 
 
EudraCT: 
2016-003930-26 
IND Number: 
77 254 
 
Protocol Number: 
DU-176b-C-U4001 
Investigational Product: 
Edoxaban (DU-176b) 
Active Ingredient(s)/INN: 
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 
 
Study Title: 
Edoxaban Versus Standard of Care and Their Effects on 
Clinical Outcomes in Patients Having Undergone 
Transcatheter Aortic Valve Implantation – In Atrial 
Fibrillation 
 
Study Acronym 
ENVISAGE-TAVI AF 
 
Study Phase: 
Phase 3b 
 
 
Indication Under 
Investigation: 
Use of Edoxaban in patients with atrial fibrillation (AF) and 
indication to chronic oral anticoagulant (OAC) medication 
after transcatheter aortic valve implantation (TAVI) 
 
 
Study Objectives: 
Co-primary objectives 
• To assess the effect of Edoxaban versus Vitamin K 
antagonist (VKA) on net adverse clinical events 
(NACE), i.e., the composite of all-cause death, 
myocardial infarction (MI), ischemic stroke, 
systemic thromboembolism (SEE), valve thrombosis, 
and major bleeding (International Society on 
Thrombosis and Haemostasis [ISTH] definition). 
• To assess the effect of Edoxaban versus VKA on 
major bleeding (ISTH definition). 
 
Secondary objectives: 
To compare Edoxaban with VKA with regards to the 
following efficacy endpoints: 
• NACE defined as the composite of all-cause death, 
MI, ischemic stroke, SEE, valve thrombosis, and 


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major and minor bleeding per Thrombolysis in 
Myocardial Infarction (TIMI) definitions 
• NACE defined as the composite of all-cause death, 
MI, ischemic stroke, SEE, valve thrombosis, and 
major bleeding (Bleeding Academic Research 
Consortium [BARC] 3 or 5 definition) 
• NACE defined as the composite of all-cause death, 
MI, ischemic stroke, SEE, valve thrombosis, and 
major and moderate bleeding (Global Utilization of 
Streptokinase and Tissue Plasminogen Activator for 
Occluded Coronary Arteries [GUSTO] definition) 
• Major Adverse Cardiac Events (MACE), defined as 
the composite of all-cause death (excluding 
adjudicated non-cardiac death), MI, or repeat 
coronary revascularization of the target lesion 
• Major Adverse Cardiac and Cerebrovascular Events 
(MACCE), defined as the composite of all-cause 
death (excluding adjudicated non-cardiac death), MI, 
stroke (ischemic, hemorrhagic, or undetermined), or 
repeat coronary revascularization of the target lesion 
• Cardiovascular mortality 
• Stroke (ischemic, hemorrhagic, or undetermined) 
• Stroke (ischemic) 
• Stroke (hemorrhagic) 
• Stroke (undetermined) 
• Fatal stroke (ischemic, hemorrhagic, or 
undetermined) 
• Non-fatal stroke (ischemic, hemorrhagic, or 
undetermined) 
• Systemic embolic event 
• Myocardial infarction 
• Valve thrombosis 
To compare Edoxaban with VKA with regards to the 
following safety endpoints: 
• Bleeding defined as TIMI major or minor, BARC 3 
or 5, and GUSTO moderate or severe 
• Bleeding defined as ISTH major and Clinically 
  
Relevant Non-major (CRNM); TIMI major/minor 
 


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bleeds or requiring medical attention; BARC 2, 3, or 
5; and GUSTO moderate or severe 
• Bleeding defined as ISTH CRNM, TIMI minor or 
requiring medical attention, BARC 2, and GUSTO 
moderate 
• All bleeding that are not ISTH major, CRNM; TIMI 
minimal; BARC 1 non-actionable; and GUSTO mild 
• Any bleeding 
• Intracranial hemorrhage 
• Life-threatening bleeding 
• Fatal bleeding (fulfilling the ISTH major bleeding 
definition) 
• Non-fatal major bleeding (ISTH definition) 
• All-cause mortality 
• Cardiovascular mortality 
• Safety parameters such as (serious) adverse events 
(S[AE]), laboratory parameters, electrocardiogram 
(ECG) and vital signs 
Other objectives: 
To compare Edoxaban with VKA with regards to the 
following: 
• Number of hospital admissions, defined as ≥ 24 h 
stay in the hospital, due to cardiovascular causes 
(post TAVI and non-TAVI procedure related), 
including but not limited to overall, for bleeding, 
SEE, venous thrombosis, shock, arrhythmia, cardiac 
rupture, stroke, aneurysms, stent occlusions, etc.) 
o Note: Hospital admissions due to 
cardiovascular causes include, but are not 
limited to the Emergency Department (ED), 
Intensive Care Unit (ICU), or 
cardiovascular ward 
• Treatment satisfaction as assessed by the Perception 
Anticoagulant Treatment Questionnaire (PACT-Q) 
• Health related quality of life as assessed by the Euro 
Quality of Life (EQ-5D-5L) Questionnaire 
• Optional: Sub-studies not interfering with the main 
  
study may be added including such as the assessment 


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of biomarkers of hemostasis/coagulation and of 
cardiovascular risk such as but not limited to whole 
blood clotting time (WBCT), thromboelastography 
(TEG), and multiple electrode aggregometry (MEA), 
high sensitivity-troponin T (Hs-TnT), growth 
differentiation factor-15 (GDF-15), and cystatin-C. 
 
Study Design: 
This is a multinational, multicenter, prospective, 
randomized, open-label study with blinded evaluation of 
endpoints (PROBE) parallel group study comparing 
Edoxaban with VKA in subjects with AF having undergone 
TAVI. Critical events will be adjudicated by an independent 
Clinical Events Committee (CEC). An independent Data 
and Safety Monitoring Board (DSMB) is responsible for 
monitoring safety during the study. 
Following signing of written informed consent, subjects are 
screened for eligibility and may be randomized from the 
evening of the day of TAVI to 5* days, i.e., until 23:59 of 
the 5th* day after the successful TAVI procedure (see 
inclusion criteria #1 for definition of “successful”) and the 
subject is qualified based on all the protocol-defined 
inclusion/exclusion criteria. The first dose of OAC should 
be administered within the 5 days after TAVI (in case of 
pacemaker deployment within the 7 days after TAVI) but 
must be administered within 24 hours post randomization, 
however NO EARLIER than the morning after successful 
TAVI. 
*If subject is waiting on a decision on pacemaker surgery, then can 
extend to 7 (7th) days 
Subjects eligible to participate in the study will be 
randomized via interactive web/voice response system 
(IXRS) such that the study will have a 1:1 ratio of subjects 
in the following study arms: 
 
• Edoxaban-based regimen: 
o Edoxaban 60 mg once-daily or 30 mg once- 
daily in subjects meeting the dose reduction 
criteria per locally approved label 
 
• VKA-based regimen: 
o The VKA of choice (any locally approved), 
dose-adjusted throughout the study to 
achieve an international normalized ratio 
  
(INR) of 2.0 to 3.0 (numbers inclusive) 
 


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[Japan: 1.6 to 2.6 in subjects aged ≥70 
(numbers inclusive)]. 
In addition to the above described oral anticoagulation 
therapy, antiplatelet management in this study shall follow 
the scenarios as outlined below: 
• Subjects having undergone TAVI without other 
potential indications for antiplatelet therapy (APT) 
may obtain either no APT or single antiplatelet 
therapy (SAPT) up to 90 days, i.e., acetylsalicylic 
acid (ASA) or any P2Y12 inhibitor (preferably 
clopidogrel). 
• Subjects having undergone TAVI with percutaneous 
coronary intervention (PCI) either prior to or during 
the study period may obtain SAPT indefinitely, i.e., 
any P2Y12 inhibitor (preferably clopidogrel) or ASA. 
Dual anti-platelet therapy (DAPT) is only allowed 
post stenting for up to 3 months after each PCI 
during this study. 
• Subjects having undergone TAVI with other 
potential indications for oral antiplatelet therapy 
may obtain either no APT or SAPT, i.e., any P2Y12 
inhibitor (preferably clopidogrel) or ASA 
indefinitely. 
The type (i.e., the international nonproprietary name, 
the dose, and the projected last dose of all antiplatelet 
agents) must be predeclared at randomization. ASA 
75-100 mg/day or generic/branded clopidogrel 75 mg/day 
(chronic therapy following loading dose) are the 
preferred agents. Type, dose, and (projected) last dose 
may be changed during the treatment period for 
documented medical reasons. 
 
Study Duration: 
Subjects will be monitored throughout the entire study 
period regardless of whether they have or have not 
experienced an endpoint. Monitoring will be performed 
with study visits (which can be on-site or at the subject’s 
current place of living, but the monitoring will be conducted 
by the Investigator or qualified designee) at 3 and 6 months 
post randomization, then semi-annually, at the end of the 
treatment period, and at 30 days after the last dose of the 
study medication (see Table 17.1). After the End of 
Treatment Visit, subjects will have the option to be followed 
  
by telephone contact with the site and/or review of their 
 


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Protocol DU176B-C-U4001 
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medical records by qualified site personnel until the end of 
the study (common study end date [CSED]). 
The enrollment will be stopped no later than at the 
attainment of a total of 320 subjects experiencing an 
adjudicated NACE across the combined treatment arms, and 
the study will continue until the last subjects enrolled will 
have accomplished the minimum treatment duration of at 
least 6 months plus their Post-treatment Follow-up Visit. 
 
Study Sites and Locations: 
It is planned to enroll approximately 1400 subjects with a 
1:1 randomization ratio (Edoxaban: VKA) approximately 
200 study sites located in the USA, Canada, Europe 
(Austria, Belgium, France, Germany, Italy, the 
Netherlands, Spain, Switzerland, UK and potentially other 
countries), and Japan. Other countries may also 
participate. 
 
Planned Sample Size: 
The primary endpoint is NACE. 
In order to determine the sample size, the following 
assumptions were made: 
• Event rate: Based on published literature and results 
from the ENGAGE AF-TIMI 48 study, it is assumed 
that the event rate of the primary efficacy endpoint of 
NACE in AF-subjects treated post TAVI with VKA 
would be 14%/year. 
• Noninferiority margin: No data were available for 
placebo-controlled studies in this subject population. 
The Executive Committee reviewed all available 
data including practice changes observed in other 
areas of cardiology on the basis of clinical studies 
and the level of statistical certainty they had 
achieved. Then it made the judgment that a 
noninferiority margin for hazard ratio 1.38 would be 
accepted by the medical community for a practice 
change given the fact that other studies have already 
supported the use of Edoxaban in subjects warranting 
anticoagulation and given its related regulatory 
approval for human use in the participating 
countries. 
• Significance level for statistical testing: 0.05. 
• Observed hazard ratio: 0.95. 
With the above assumptions, to demonstrate noninferiority 
with 80% of power, the study needs to collect at least 
 


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320 NACE across the combined study arms. With an 
anticipated median follow-up time of two years and an 
annual event rate of 14%, a total of approximately 
1400 subjects need to be randomized. 
The sample size is event driven. The sample size or the 
duration of follow-up may require adjustment based on the 
actual vs. anticipated primary endpoint event and drop-out 
rates. 
 
Subject Eligibility Criteria: Inclusion criteria 
Subjects must satisfy all of the following criteria to be 
included in the study: 
1. Successful TAVI via transvascular access routes 
such as femoral, carotid, axillary, and subclavian 
arteries. Other access routes need prior approval per 
majority vote from 3 members of the Executive 
Committee (both Global Lead Investigators and the 
Daiichi Sankyo Medical Lead or his/her designee). 
Success is defined as: 
a. Correct positioning of a single prosthetic 
heart valve into the proper anatomical 
location 
b. Presence of all 3 conditions post TAVI 
i. Mean aortic valve gradient 
<20 mm Hg 
ii. Peak transvalvular velocity <3.0 m/s 
iii. Aortic valve regurgitation of 2 or less 
c. No clinically overt stroke 
d. No uncontrolled bleeding at time of 
randomization 
2. Indication for chronic OAC 
a. Documented pre-existing AF 
b. New onset AF (e.g., > 30 seconds 
documented by ECG) 
3. Provision of signed informed consent 
4. Age ≥18 years 
 


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Exclusion criteria 
Bleeding risks or systemic conditions 
1. Conditions with a high risk of bleeding 
o This may include but is not limited to: active 
peptic ulcer with upper gastrointestinal 
bleeding within last 90 days prior to 
randomization, malignancy at high risk of 
bleeding, major intraspinal or intracerebral 
vascular abnormalities, recent unresolved 
brain or spinal injury, or spinal surgery 
(recent = within the last 90 days prior to 
randomization), any intracranial hemorrhage, 
known or suspected esophageal varices, 
arteriovenous malformations, or clinically 
relevant vascular aneurysms 
2. Other known bleeding diathesis 
3. Conditions that make it difficult for the subject to 
swallow the study medication 
 
Procedure related 
4. Serious unresolved periprocedural complications 
 
Medication related 
5. Any contraindication to EITHER Edoxaban OR 
VKA per local label; this includes hypersensitivity 
to the active ingredient, to any of the excipients, or 
any of the components of the study medications 
6. Concomitant treatment with other antithrombotic 
agents ASA > 100 mg/day, fibrinolytic therapy, or 
chronic (> 4 days/week) use of nonsteroidal anti- 
inflammatory drugs (NSAIDs); however, NSAID 
patches are permitted 
7. Requirement for dual antiplatelet therapy (DAPT) at 
randomization that will be indicated for more than 
3 months beyond the first study dose of OAC 
8. Treatment with other investigational (i.e., non- 
approved) drugs or devices within 30 days before 
enrollment or planned use of investigational drugs 
or devices during the study 
 
 
 


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Concomitant conditions and therapies 
9. Clinically overt stroke within the last 90 days before 
TAVI 
10. Any scheduled drug or device-based therapy during 
the treatment period that would eliminate the need 
for chronic oral anticoagulation (any other 
diagnostic or therapeutic procedure that is associated 
with temporary interruption of OAC is permitted) 
11. (former exclusion criteria 11 is no longer 
applicable, numbers not adjusted to keep alignment 
with version 2.0 of the protocol) 
12. Any bail out catheter based on cardiac interventional 
procedure during the index TAVI (however, during 
the same session as TAVI (pre or post TAVI) 
scheduled PCI and angioplasty of the iliac/femoral 
arteries are permitted) 
13. Subjects with mechanical heart valves 
14. Mitral valve stenosis Grade III-IV/IV (moderate to 
severe/severe); however, subjects with moderate 
mitral valve stenosis may be enrolled into the study 
15. Active infective endocarditis 
16. Major surgery within 30 days prior to randomization 
17. (former exclusion criteria 17 is no longer 
applicable, numbers not adjusted to keep alignment 
with version 2.0 of the protocol) 
18. ST-elevation myocardial infarction within 30 days 
prior to TAVI until randomization (non-ST- 
elevation myocardial infarction is no exclusion) 
19. End stage renal disease (creatinine clearance 
< 15 mL/min or dialysis) at randomization 
20. Severe hepatic impairment or hepatic disease 
associated with coagulopathy (e.g., acute/chronic 
active hepatitis or cirrhosis, Child Pugh B, C) 
21. Uncontrolled severe hypertension documented by 
repeated BP of ≥170/100 mmHg, despite medical 
intervention 
22. Respiratory failure requiring mechanical ventilation 
at time of randomization 
 


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23. Critically ill or hemodynamically unstable subjects 
at the time of randomization, (i.e., cardiogenic 
shock, acute heart failure, including the requirement 
for pharmacologic treatment or mechanical support 
to assist circulation) 
24. Active malignancy (requiring chemotherapy, 
radiation or surgery at the time of randomization) 
except for adequately treated non-melanoma skin 
cancer or other noninvasive or in situ neoplasms 
(e.g., cervical cancer in situ that has been 
successfully treated); anti-hormonal therapy is 
allowed 
 
Other exclusion criteria 
25. Any of the following abnormal local laboratory 
results at the time of randomization: 
a. Platelet count < 50 x109/L 
b. Hemoglobin < 8 g/dL (5 mmol/L at 
randomization, no ongoing bleeding, no 
blood transfusion of whole blood or red 
blood cells within 24 hours); however, for 
subjects with a history of hemoglobin of no 
less than 7.5 g/dL while taking chronic 
OAC, the exclusion will be based on 
hemoglobin of < 7.5 g/dL 
26. Female subjects of childbearing potential without 
using highly effective methods of contraception 
(i.e., a method of contraception with a failure rate < 
1 % during the course of the study, including the 
follow up period). A female of childbearing 
potential is defined as one who has not been 
postmenopausal for at least one year, or has not been 
surgically sterilized, or has not had a hysterectomy 
at least three months prior to the start of this study 
[Visit 1]). Females taking oral contraceptives 
should have been on that therapy for at least three 
months. Highly effective methods of contraception 
includes 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); 
 


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Dosage Form, Dose and 
Route of Administration: 
Protocol DU176B-C-U4001 
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bilateral tubal occlusion; vasectomized partner; 
along with barrier methods of contraception (male 
condom, female condom, cervical cap, diaphragm, 
contraceptive sponge) 
27. Pregnant or breast-feeding subjects 
28. Assessment by the Investigator that the subject is 
not likely to comply with the study procedures or 
will complete follow-up 
29. Current participation in another clinical study 
(unless the registry DOES NOT interfere with the 
evaluation of ENVISAGE-TAVI-AF as per this 
protocol. Before including such a subject, the 
Investigator shall discuss the situation with the 
Daiichi Medical Lead or his/her designee) 
30. Previous randomization in this study 
31. Drug or alcohol dependence within the past 
12 months prior to randomization as judged by the 
Investigator 
32. Life expectancy less than 6 months beyond the 
targeted last visit 
33. Subjects with antiphospholipid syndrome who are 
triple positive (for lupus anticoagulant, 
anticardiolipin antibodies, and anti-beta 2- 
glycoprotein I antibodies) with thrombosis 
 
Edoxaban: 60 mg and 30 mg film-coated tablets for 
once-daily oral use, and 15 mg film-coated tablets for 
transitioning at end of treatment will be provided by the 
Sponsor. Dosing must follow the locally approved label. 
VKA: Oral VKA tablets as selected and provided by the site 
or prescribed by treating physician and used in accordance 
with the local label to obtain an INR of 2.0 to 3.0 (numbers 
inclusive) [Japan: 1.6 to 2.6 in subjects aged ≥70 (numbers 
inclusive)]. 
It is the Investigator’s responsibility throughout the study to 
collect INR as per medical needs, preferably monthly. The 
Investigator will monitor the INR and adjust the VKA dose 
to maintain the INR within target (2.0 to 3.0 (numbers 
inclusive) [Japan: 1.6 to 2.6 in subjects aged ≥70 (numbers 
inclusive)]), unless performed by the subject’s treating 
physician. The Investigator will record any changes in VKA 
dosage within the electronic case report form (eCRF). 
 
 


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Protocol DU176B-C-U4001 
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P2Y12 antagonist: Clopidogrel (generic or branded) 75 mg, 
commercially/locally available tablets for once-daily oral 
use will be provided by the site. 
Acetylsalicylic acid (ASA): 75-100 mg for once-daily oral 
use will be provided by the site. 
Note: Sponsor supplies sites with only Edoxaban study 
medication: Edoxaban 60 mg and 30 mg film-coated tablets 
for once-daily oral use, and 15 mg film-coated tablets for 
transitioning at end of treatment. Sites or treating physicians 
will provide or prescribe: VKA, clopidogrel, and ASA as per 
local standard of care and as specified in the protocol. 
Please refer to the locally approved label for the summary of 
product characteristics (SmPC) of each study drug. 
 
Study Endpoints: 
Primary efficacy endpoint: 
• NACE, i.e., the composite of all-cause death, MI, 
ischemic stroke, SEE, valve thrombosis, and major 
bleeding (ISTH definition) 
 
Primary safety endpoint: 
• Major bleeding (ISTH definition) 
Secondary efficacy endpoints: 
• NACE defined as the composite of all-cause death, 
MI, ischemic stroke, SEE, valve thrombosis, and 
major bleeding (TIMI definition) 
• NACE defined as the composite of all-cause death, 
MI, ischemic stroke, SEE, valve thrombosis, and 
major bleeding ([BARC 3 or 5 definition) 
• NACE defined as the composite of all-cause death, 
MI, ischemic stroke, SEE, valve thrombosis, and 
major and moderate bleeding (GUSTO definition) 
• Major Adverse Cardiac Events (MACE), defined as 
the composite of all-cause death (excluding 
adjudicated non-cardiac death), MI, or repeat 
coronary revascularization of the target lesion 
• Major Adverse Cardiac and Cerebrovascular Events 
(MACCE), defined as the composite of all-cause 
death (excluding adjudicated non-cardiac death), MI, 
stroke (ischemic, hemorrhagic, or undetermined), or 
repeat coronary revascularization of the target lesion 
 


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• Cardiovascular mortality 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
• Stroke (ischemic, hemorrhagic, or undetermined) 
• Stroke (ischemic) 
• Stroke (hemorrhagic) 
• Stroke (undetermined) 
• Fatal stroke (ischemic, hemorrhagic, or 
undetermined) 
• Non-fatal stroke (ischemic, hemorrhagic, or 
undetermined) 
• SEE 
• Myocardial Infarction 
• Valve thrombosis 
Secondary safety endpoints: 
• Bleeding defined as TIMI major or minor, BARC 3 
or 5, and GUSTO moderate or severe) 
• Bleeding defined as ISTH major and CRNM, TIMI 
major/minor bleeds or requiring medical attention, 
BARC 2, 3 or 5, and GUSTO moderate or severe 
• Bleeding defined as ISTH CRNM, TIMI minor or 
requiring medical attention, BARC 2, and GUSTO 
moderate 
• All bleeding that are not ISTH major, CRNM; TIMI 
minimal; BARC 1 non-actionable; and GUSTO mild 
• Any bleeding 
• Intracranial hemorrhage 
• Life-threatening bleeding 
• Fatal bleeding (fulfilling the ISTH major bleeding 
definition) 
• Non-fatal major bleeding (ISTH definition) 
• All-cause mortality 
• Cardiovascular mortality 
• Safety parameters such as (serious) adverse events, 
laboratory parameters, ECG and vital signs 
 


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Other endpoints: 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
• Number of hospital admissions, defined as ≥ 24 h 
stay in the hospital, due to cardiovascular causes 
(post TAVI and non-TAVI procedure related), 
including for bleeding, SEE, venous thrombosis, 
shock, arrhythmia, cardiac rupture, stroke, 
aneurysms, stent occlusions, etc.). 
o Hospital admissions due to cardiovascular 
causes include, but are not limited to the 
Emergency Department (ED), Intensive Care 
Unit (ICU), and cardiovascular ward. 
• Treatment satisfaction as assessed by the Perception 
Anticoagulant Treatment Questionnaire (PACT-Q) 
• Health related quality of life as assessed by the 
EuroQoL (EQ-5D-5L) Questionnaire 
• Optional: Sub-studies not interfering with the main 
study may be added including such as the assessment 
of biomarkers of hemostasis such as but not limited 
to markers of coagulation and aggregation (sub 
study), WBCT, TEG, and MEA)], or of 
cardiovascular and overall prognosis. 
 
Statistical Analyses: 
Four analysis sets are defined: 
• The Intention-to-treat (ITT) analysis set consists of 
all randomized subjects irrespective of whether they 
received a single dose of study Edoxaban or VKA or 
not. 
• The modified 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 
randomized 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 (for more details, see Section 11.1.3): 
- 
A major violation of the inclusion criteria 
- 
An unequivocal violation of the exclusion criteria 
• The Safety analysis set (SAF) consists of all 
randomized subjects who received at least one dose 
of the study Edoxaban or study VKA according to 
IXRS assignment. 
 


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Definition of terms: 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
’Overall Study Period’: This period is defined as the time 
from the reference date* up to an estimated Month 36 /end of 
treatment (EOT) (Visit 8). 
’Overall Study Period + 30 days’: This period is defined as 
the time from the reference date* and time of randomization 
up to an estimated Month 36 /EOT (Visit 8) + 30 days, i.e., 
to Month 37 (post treatment follow-up visit). 
‘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 and time of 
final dose of study Edoxaban or study VKA plus 30 days, 
including study regimen interruptions. 
(*) When using the ITT analysis set, the reference date is the 
date/time of randomization; otherwise, the reference date is 
the date of first intake of study Edoxaban or study VKA. 
 
Planned Analyses: 
There are 4 primary hypotheses that will be tested in 
hierarchical 
order: 
• Hypothesis (1): 
o The Edoxaban-based regimen is noninferior 
to the VKA-based regimen with regards to 
NACE. 
• Hypothesis (2): 
o The Edoxaban-based regimen is noninferior 
to the VKA-based regimen with regards to 
major bleeding (ISTH definition). 
• Hypothesis (3): 
o The Edoxaban-based regimen is superior to 
the VKA-based regimen with regards to 
major bleeding (ISTH definition). 
• Hypothesis (4): 
o The Edoxaban-based regimen is superior to 
the VKA-based regimen with regards to 
NACE. 
The analysis sets and analysis periods to be used for the 
main analyses related to these four hypotheses are presented 
below: 
 


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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
 
Hypothesi 
s 
Endpoint 
Primary 
Analysis 
Set 
Primary 
Analysis 
Period 
(1) 
NACE 
ITT 
Overall study 
period 
(2) 
Major 
bleeding 
(ISTH def) 
ITT 
Overall study 
period 
(3) 
Major 
bleeding 
(ISTH def) 
ITT 
Overall study 
period 
(4) 
NACE 
ITT 
Overall study 
period 
To control the type-I error rate, these four hypotheses will be 
tested in a hierarchical manner: 
• Step (1): The Edoxaban-based regimen will be 
considered noninferior to the VKA-based regimen 
with regards to NACE, if the upper boundary of the 
two-sided 95% CI for hazard ratio (HR) falls below 
1.38. If it is significant, then go to Step (2), 
otherwise stop here. 
• Step (2): The Edoxaban-based regimen will be 
considered noninferior to the VKA-based regimen 
with regards to major bleeding (ISTH def.), if the 
upper boundary of the two-sided 95% confidence 
interval (CI) for HR falls below 1.38. If it is 
significant, then go to Step (3), otherwise stop here. 
• Step (3): The Edoxaban-based regimen will be 
considered superior to the VKA-based regimen with 
regards to major bleeding (ISTH def.), if the upper 
boundary of the two-sided 95% CI for HR falls 
below 1.00. If it is significant, then go to Step (4), 
otherwise stop here. 
• Step (4): The Edoxaban-based regimen will be 
considered superior to the VKA-based regimen with 
regards to NACE, if the upper boundary of the two- 
sided 95% CI for HR falls below 1.00. 
For each of the primary and secondary adjudicated 
endpoints, appropriate summary statistics (e.g., event rate) 
including 95% CI will be provided. 


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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
 
For each of the adjudicated 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 randomization (IXRS) as 
covariates, (dose adjustment [yes, no], to provide point 
estimates and 95% CI for the 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. 
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’ and 
‘overall study period + 30 days’ will be presented but should 
be interpreted in a more descriptive way. 
For time to first event analyses, cumulative event rates over 
time are summarized using the Kaplan-Meier method as 
appropriate. 
The main analyses for all secondary efficacy and safety 
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 applying 
the aforementioned statistical method. 
There will be no formal statistical testing for secondary or 
other exploratory endpoints. Hazard ratios, CI, and p-values 
are provided but should be interpreted in a purely descriptive 
exploratory manner. 
 


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TABLE OF CONTENTS 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
INVESTIGATOR AGREEMENT......................................................................... 2 
INVESTIGATOR’S SIGNATURE ....................................................................... 3 
CRITICAL STUDY CONTACTS LIST ............................................................... 4 
PROTOCOL SYNOPSIS ....................................................................................... 5 
TABLE OF CONTENTS ..................................................................................... 22 
LIST OF TABLES ............................................................................................... 28 
LIST OF FIGURES ............................................................................................. 28 
LIST OF ABBREVIATIONS .............................................................................. 29 
DEFINITIONS SPECIFIC TO THIS PROTOCOL ............................................ 31 
1. 
INTRODUCTION ............................................................................ 32 
1.1. 
Background ....................................................................................... 32 
1.2. 
Study Rationale ................................................................................. 34 
1.2.1. 
Dose Rationale .................................................................................. 34 
1.3. 
Risks and Benefits for Study Subjects .............................................. 34 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................. 35 
2.1. 
Study Objectives ............................................................................... 35 
2.1.1. 
Co-Primary Objectives ..................................................................... 35 
2.1.2. 
Secondary Objectives ....................................................................... 35 
2.1.3. 
Other objectives: ............................................................................... 36 
2.2. 
Study Hypothesis .............................................................................. 37 
3. 
STUDY DESIGN ............................................................................. 38 
3.1. 
Overall Design .................................................................................. 38 
3.2. 
Discussion of Study Design .............................................................. 39 
4. 
STUDY POPULATION ................................................................... 41 
4.1. 
Inclusion Criteria .............................................................................. 41 
4.2. 
Exclusion Criteria ............................................................................. 41 
4.2.1. 
Bleeding risks or systemic conditions .............................................. 41 
4.2.2. 
Procedure related .............................................................................. 42 
4.2.3. 
Medication related ............................................................................ 42 
4.2.4. 
Concomitant conditions and therapies .............................................. 42 
4.2.5. 
Other exclusion criteria ..................................................................... 43 


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Protocol DU176B-C-U4001 
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5. 
STUDY TREATMENT(S) ............................................................... 45 
5.1. 
Assigning Subjects to Treatments and Blinding ............................... 45 
5.1.1. 
Treatment Group(s) .......................................................................... 45 
5.1.2. 
Method of Treatment Allocation ...................................................... 46 
5.1.3. 
Blinding ............................................................................................ 46 
5.2. 
Study Drug(s) .................................................................................... 46 
5.2.1. 
Description ........................................................................................ 46 
5.2.1.1. 
Edoxaban: ......................................................................................... 47 
5.2.1.2. 
VKA .................................................................................................. 48 
5.2.1.3. 
P2Y12 antagonist ............................................................................... 50 
5.2.1.4. 
Acetylsalicylic acid (ASA) ............................................................... 50 
5.2.2. 
Supply of Medications ...................................................................... 50 
5.2.3. 
cLabeling and Packaging .................................................................. 50 
5.2.4. 
Preparation ........................................................................................ 50 
5.2.5. 
Administration .................................................................................. 50 
5.2.6. 
Storage .............................................................................................. 51 
5.2.7. 
Edoxaban Accountability .................................................................. 51 
5.3. 
Control Treatment ............................................................................. 52 
5.4. 
Dose Reductions ............................................................................... 52 
5.5. 
Method of Assessing Treatment Compliance ................................... 52 
5.6. 
Prior and Concomitant Medications ................................................. 52 
5.7. 
Prohibited Medications ..................................................................... 53 
5.8. 
Subject Withdrawal/Discontinuation ................................................ 54 
5.8.1. 
Reasons for Study Drug Interruption/Discontinuation ..................... 54 
5.8.2. 
Subjects with Study Drug Interruptions/Discontinuations ............... 55 
5.8.3. 
Withdrawal of Consent from Study Participation............................. 56 
5.8.4. 
Subject Replacement ........................................................................ 57 
5.8.5. 
Subject Re-screening Procedures ...................................................... 57 
6. 
STUDY PROCEDURES .................................................................. 58 
6.1. 
Screening Visit .................................................................................. 58 
6.2. 
Randomization Visit (Day 1) ............................................................ 58 
6.3. 
Prior to Discharge or Transfer to Another Hospital or Hospital 
Department ....................................................................................... 60 


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Protocol DU176B-C-U4001 
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6.4. 
Continued Treatment Visits .............................................................. 60 
6.5. 
End of Treatment (EOT) Visit .......................................................... 61 
6.5.1. 
Transition from Study Medication to Standard of Care VKA .......... 62 
6.6. 
Post-treatment Follow-up Visit ......................................................... 63 
6.7. 
Post Discontinuation/Follow-up Contact .......................................... 63 
7. 
OUTCOME ASSESSMENTS .......................................................... 64 
7.1. 
Bleeding ............................................................................................ 64 
7.2. 
Primary Efficacy Parameters ............................................................ 64 
7.3. 
Primary Safety Parameters ................................................................ 64 
7.4. 
Secondary Endpoints (All Exploratory) ........................................... 64 
7.4.1. 
Secondary Efficacy Endpoints .......................................................... 64 
7.4.2. 
Secondary Safety Endpoints ............................................................. 65 
7.4.3. 
Other Endpoints ................................................................................ 65 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS............................................................................... 66 
8.1. 
Immunogenicity ................................................................................ 66 
8.2. 
Pharmacogenomic Analyses ............................................................. 66 
9. 
SAFETY EVALUATION AND REPORTING ............................... 67 
9.1. 
Adverse Event Collection and Reporting ......................................... 67 
9.1.1. 
Bleeding ............................................................................................ 68 
9.2. 
Events of Special Interest ................................................................. 69 
9.2.1. 
Combined Elevations of Aminotransferases and Bilirubin .............. 69 
9.2.2. 
Reporting of Pregnancy/ Exposure in Utero ..................................... 70 
9.3. 
Adverse Event ................................................................................... 70 
9.3.1. 
Definition of Adverse Event ............................................................. 70 
9.3.2. 
Unexpected Adverse Event ............................................................... 71 
9.3.3. 
Expected Adverse Event ................................................................... 71 
9.3.4. 
Serious Adverse Event ...................................................................... 71 
9.3.5. 
Severity Assessment ......................................................................... 72 
9.3.6. 
Causality Assessment ....................................................................... 72 
9.3.7. 
Action Taken Regarding Study Drug(s) ........................................... 72 
9.3.8. 
Other Action Taken for Event .......................................................... 73 
9.3.9. 
Adverse Event Outcome ................................................................... 73 


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Protocol DU176B-C-U4001 
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9.4. 
Timing of Adverse Event Reporting ................................................. 73 
9.5. 
Reporting SAEs/AEs ........................................................................ 74 
9.5.1. 
Documentation .................................................................................. 74 
9.6. 
Serious Adverse Event Reporting–Procedure for Investigators ....... 74 
9.7. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee ..................................................... 75 
9.8. 
Exposure In Utero During Clinical Studies ...................................... 76 
9.9. 
Clinical Laboratory Evaluations ....................................................... 76 
9.10. 
Vital Signs ........................................................................................ 76 
9.11. 
Electrocardiograms ........................................................................... 77 
9.12. 
Physical Examinations ...................................................................... 77 
10. 
OTHER ASSESSMENTS ................................................................ 78 
10.1. 
Healthcare Resource Utilization ....................................................... 78 
10.2. 
Perception Anticoagulant Treatment Questionnaire (PACT-Q) ....... 78 
10.3. 
EuroQoL (EQ-5D-5L) Questionnaire ............................................... 78 
11. 
STATISTICAL METHODS ............................................................. 80 
11.1. 
Analysis Sets ..................................................................................... 80 
11.1.1. 
Intention-to-treat Analysis Set .......................................................... 80 
11.1.2. 
Modified Intention-to-treat Analysis Set .......................................... 80 
11.1.3. 
Per Protocol Analysis Set ................................................................. 80 
11.1.4. 
Safety Analysis Set ........................................................................... 81 
11.2. 
General Statistical Considerations .................................................... 81 
11.3. 
Study Population Data ...................................................................... 82 
11.4. 
Statistical Analyses ........................................................................... 83 
11.4.1. 
Analysis of the primary endpoint(s) ................................................. 83 
11.4.2. 
Analyses of the secondary exploratory endpoints ............................ 85 
11.4.3. 
Pharmacokinetic/Pharmacodynamic Analyses ................................. 85 
11.4.3.1. 
Pharmacokinetic Analyses ................................................................ 85 
11.4.3.2. 
Pharmacodynamic Analyses ............................................................. 85 
11.4.3.3. 
Biomarker Analyses .......................................................................... 85 
11.4.3.4. 
Pharmacogenomic Analyses ............................................................. 85 
11.4.4. 
Health Economics Outcome Research (HEOR) Analyses................ 85 
11.5. 
Safety Analyses................................................................................. 86 


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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
11.5.1. 
Adverse Event Analyses ................................................................... 86 
11.5.2. 
Clinical Laboratory Evaluation Analyses ......................................... 86 
11.5.3. 
Vital Sign Analyses .......................................................................... 87 
11.5.4. 
Physical Examination Analyses ........................................................ 87 
11.5.5. 
Electrocardiogram Analyses ............................................................. 87 
11.6. 
Other Analyses .................................................................................. 87 
11.7. 
Interim Analyses ............................................................................... 87 
11.8. 
Data and Safety Monitoring Board (DSMB) .................................... 87 
11.9. 
Sample Size Determination .............................................................. 88 
11.10. 
Statistical Process ............................................................................. 88 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE .................... 89 
12.1. 
Monitoring and Inspections .............................................................. 89 
12.2. 
Data Collection ................................................................................. 89 
12.3. 
Data Management ............................................................................. 90 
12.4. 
Study Documentation and Storage ................................................... 90 
12.5. 
Record Keeping ................................................................................ 91 
13. 
FINANCING AND INSURANCE ................................................... 92 
13.1. 
Finances ............................................................................................ 92 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................... 92 
14. 
PUBLICATION POLICY ................................................................ 93 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .... 94 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance ............ 94 
15.2. 
Subject Confidentiality ..................................................................... 94 
15.3. 
Informed Consent ............................................................................. 94 
15.4. 
Regulatory Compliance .................................................................... 95 
15.5. 
Protocol Deviations .......................................................................... 96 
15.6. 
Supply of New Information Affecting the Conduct of the Study ..... 96 
15.7. 
Protocol Amendments ...................................................................... 97 
15.8. 
Study Termination ............................................................................ 97 
15.9. 
Data and Safety Monitoring Board ................................................... 97 
15.10. 
Clinical Events Committee ............................................................... 98 
15.11. 
Executive Committee ........................................................................ 98 
15.12. 
Steering Committee .......................................................................... 98 


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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
15.13. 
Operations Committee ...................................................................... 98 
15.14. 
Sub-studies ........................................................................................ 98 
15.15. 
Address List ...................................................................................... 99 
16. 
REFERENCES ............................................................................... 100 
17. 
APPENDICES ................................................................................ 103 
17.1. 
Bleeding Criteria ............................................................................. 108 
17.1.1. 
ISTH Bleeding Criteria ................................................................... 108 
17.1.1.1. 
Definitions of terms ........................................................................ 108 
17.1.2. 
TIMI (Non-CABG) ......................................................................... 109 
17.1.3. 
BARC Bleed Scoring28 ................................................................... 110 
17.1.4. 
GUSTO Definitions29 ..................................................................... 111 
17.2. 
Myocardial Infarction (Varac-2 & ESC/Third Universal) .............. 111 
17.3. 
Cerebrovascular event .................................................................... 113 
17.3.1. 
Stroke is classified according to the VARC-2 definitions. ............. 113 
17.3.2. 
ECASS I Criteria [European Cooperative Acute Stroke Study 
(ECASS) ......................................................................................... 114 
17.4. 
Valve thrombosis ............................................................................ 114 
17.4.1. 
Assessment of the occurrence of bioprosthetic valve thrombosis is 
based on Mylotte:30 ......................................................................... 115 
17.5. 
Systemic thromboembolism ........................................................... 115 
17.6. 
User Guide for EQ-5D-5L .............................................................. 115 
17.7. 
Calculation of Creatinine Clearance (CrCL) .................................. 115 


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LIST OF TABLES 
 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
Table 5.1: Transitioning to Edoxaban at Randomization .................................. 47 
Table 5.2: Transitioning from Edoxaban at EOT .............................................. 47 
Table 5.3: Transitioning to Study VKA at Randomization................................ 49 
Table 5.4: Transitioning from Study VKA at EOT ........................................... 49 
Table 11.1: Statistical Analysis Hierarchy for Primary Parameters .................... 84 
Table 17.1: Table of Events of Treatment Period .............................................. 104 
Table 17.2: ISTH Bleeding Criteria27 ................................................................ 108 
Table 17.3: Myocardial Infarction (MI) According to the VARC-2 
Definitions ...................................................................................... 111 
Table 17.4: Myocardial Infarction (MI) According to the ESC Criteria/Third 
Universal Definition ....................................................................... 112 
 
 
 
 
LIST OF FIGURES 
Figure 3.1: ENVISAGE-TAVI AF Study Design ............................................... 39 


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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
LIST OF ABBREVIATIONS 
 
ACRONYM 
DEFINITION 
AE 
Adverse Event 
AF 
Atrial fibrillation 
ALT 
Alanine transaminase 
APT 
Antiplatelet therapy 
ASA 
Acetylsalicylic acid (aspirin) 
AST 
Aspartate transaminase 
BARC 
Bleeding Academic Research Consortium 
CBC 
Complete blood count 
CEC 
Clinical events committee 
CrCL 
Creatinine clearance 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
DAPT 
Dual antiplatelet therapy 
DSMB 
Data safety monitoring board 
EC 
Executive Committee (unless used as part of a European Commission 
Directive) 
ECG 
Electrocardiogram 
ED 
Emergency Department 
EOT 
End of treatment 
EQ-5D-5L 
EuroQuality of Life (EQ-5D-5L) Questionnaire 
EtC 
Ethics Committee 
GCP 
Good Clinical Practice 
GDF-15 
Growth differentiation factor-15 
GUSTO 
Global Utilization of Streptokinase and Tissue Plasminogen Activator 
for Occluded Coronary Arteries 
Hb 
Hemoglobin 
HEOR 
Health economics and outcomes research 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard ratio 
Hs-TnT 
High sensitivity troponin T 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ICU 
Emergency Care Unit 
INN 
International Nonproprietary Name 
INR 
International Normalized Ratio 
IRB 
Institutional review board 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
Intention-to-treat 
IXRS 
Interactive web/voice response system 
MEA 
Multiple electrode aggregometry 


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Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
 
ACRONYM 
DEFINITION 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mITT 
Modified intention to treat 
MLBCs 
Major late bleeding complications 
NACE 
Net adverse clinical events 
NSAID 
Nonsteroidal anti-inflammatory drug 
OAC 
Oral anticoagulant(s) 
OAP 
Oral antiplatelet 
PACT-Q 
Perception of Anticoagulant Treatment Questionnaire 
PCI 
Percutaneous coronary intervention 
P-gp 
P-glycoprotein 
PP 
Per protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAPT 
Single antiplatelet therapy 
SEE 
Systemic embolic event 
SmPC 
Summary of product characteristics 
SOP 
Standard operating procedures 
STS 
Society of Thoracic Surgeons 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAVI 
Transcatheter aortic valve implantation 
TEAE 
Treatment-emergent adverse event 
TEE 
Transesophageal echocardiography or transesophageal echocardiogram 
TEG 
Thromboelastography 
TIMI 
Thrombolysis in Myocardial Infarction 
TTE 
Transthoracic echocardiography or transthoracic echocardiogram 
ULN 
Upper limit of normal 
VKA 
Vitamin K antagonist 
WBCT 
Whole blood clotting time 
WHO 
World Health Organization 


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Protocol DU176B-C-U4001 
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DEFINITIONS SPECIFIC TO THIS PROTOCOL 
 
Term 
Definition for this protocol 
Discontinuation 
Permanent stoppage of study medication. The subject will 
not be allowed to restart study medication and should follow 
the transition procedures outlined in Section 5.2.1.1.2 or 
Section 5.2.1.2.2. 
Interruption 
A temporary stoppage of study medication. The subject is 
allowed to restart the study medication at the discretion of 
the Investigator. 
End of TAVI 
The clock for randomization starts with the removal of the 
sheath with hemostasis 
End of Study 
As an event driven study, enrollment will be stopped no 
later than at the attainment of a total of 320 subjects 
experiencing an adjudicated NACE across the combined 
treatment arms, and, the study will continue until the last 
subjects enrolled will have accomplished the minimum 
treatment duration of at least 6 months plus their Post- 
treatment Follow-up Visit. 
This Visit by the last subject enrolled will be defined as 
theend of the study (or common study end date [CSED]. 
Major bleeding 
Major bleeding is considered to include life-threatening and 
fatal bleeding. 
Study drugs 
Any study medication or prescribed oral antiplatelet (OAP) 
co-administered medication is defined within this protocol 
as a study drug. 
Study medication 
The primary medications within this study are Edoxaban 
and VKA, referred to as study medications. The OAP 
co-administered medications (P12Y2 inhibitors or ASA) for 
the purpose of this protocol are NOT referred to as study 
medications; however, they are included within the term 
study drugs (see above). 
Valve Thrombosis 
Any thrombus attached to or near an implanted valve that 
occludes part of the blood flow path, interferes with valve 
function, or is sufficiently large to warrant treatment. Note 
that valve-associated thrombus identified at autopsy in a 
subject whose cause of death was not valve-related should 
not be reported as valve thrombosis. 


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1. 
INTRODUCTION 
1.1. 
Background 
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Degenerative aortic valve stenosis is the second most common valvular disorder in 
Europe and in the United States.1 Its pathogenesis involves chronic valvular tissue 
inflammation, lipoprotein deposition, osteoblast activation, and extracellular 
calcifications.2 Transcatheter aortic valve implantation (TAVI) is a life-saving procedure 
for patients (est. 48,000 completed in 2014 EU/US)1,2 with severe aortic stenosis and 
high, or prohibitive risk for surgery.3,4 The use of TAVI for the treatment of aortic 
insufficiency/aortic valve regurgitation has also provided efficacious clinical outcomes.5,6 
The safety and effectiveness of TAVI compared with surgical aortic valve replacement 
has been demonstrated in clinical randomized trials using both of the two most 
commonly used TAVI devices, the balloon-expandable Edwards Sapien / SAPIEN XT 
valve (Edwards Sapien, CA) and the Medtronic Core Valve Revalving System 
(Medtronic Inc., CA) (4-6).4,7,8 
Bleeding complications and cerebrovascular events following TAVI are a matter of 
concern. As compared to percutaneous coronary interventions (PCI), this risk is at least 
10-fold higher for TAVI.9 Patients undergoing TAVI are elder, frail, and at high risk for 
both stroke (high CHA2DS2-VASc score or CHADS2) and bleeding (high HAS-BLEED 
Score) though at present, studies are underway, that compare the outcome of TAVI 
versus surgical valve replacement in patients of less overall risk.10 This risk increases 
exponentially in patients with atrial fibrillation or other indications to chronic 
anticoagulation therapy. Balancing the risk of both bleeding and thrombotic events in 
this population is challenging. Moreover, optimal antithrombotic therapy after TAVI is 
still unknown. Cerebral imaging studies have shown a very high incidence of new 
ischemic lesions after TAVI, irrespective of the device or access-site used. The highest 
risk for embolic cerebrovascular events occurs within 3-6 months after valve 
implantation. Furthermore, new-onset atrial fibrillation may account for many episodes 
of stroke at distance from the TAVI procedure. Bleeding complications are associated 
with significant morbidity and mortality after TAVI. However, not all bleeding 
complications are mechanical in origin. Many patients require blood transfusions after 
TAVI despite the absence of an obvious source of bleeding. Moreover, in patients with 
indication to anticoagulation, VKA exposes such patients to an excessive risk for 
bleeding. Edoxaban is an oral, reversible, direct factor Xa inhibitor with a linear and 
predictable pharmacokinetic profile. In the ENGAGE AF-TIMI 48 study both the 
higher-dose Edoxaban regimen (60 mg) and lower-dose Edoxaban regimen (30 mg) 
demonstrated to be noninferior to warfarin with respect to the prevention of stroke or 
systemic embolism and were associated with significantly lower rates of bleeding and 
death from cardiovascular causes in a study of 21 105 patients with moderate-to-high risk 
atrial fibrillation. Therefore, the use of a direct factor Xa inhibitor such as Edoxaban in 
patients undergoing TAVI may be an attractive option in order to prevent 
thromboembolic and bleeding events. 
Periprocedural access-site bleeding after TAVI is common and is associated with a 
significant impact on morbidity and mortality. Given the advanced age and the presence 


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of multiple comorbidities including atrial fibrillation (AF) or coronary artery disease 
among the currently treated TAVI population, such patients are at higher risk of late 
(> 30 days) bleeding. Généreux et al. in a pooled analysis from the PARTNER trials and 
registries characterized the incidence, impact, and predictors of late bleeding following 
TAVI.11 Among 2401 patients who underwent TAVI and survived to 30 days, major late 
bleeding complications (MLBCs) occurred in 142 (5.9%) at a median time of 132 days. 
The most common causes of MLBCs were gastrointestinal (40.8%) and neurological 
(15.5%) bleedings. Predictors of MLBCs were atrial fibrillation, left ventricular mass, 
moderate to severe paravalvular leak and baseline hemoglobin. The MLBCs occurring 
between 30 days and 1 year were associated with significantly higher rates of death, 
cardiac death, major stroke, renal failure and rehospitalization. The MLBC was a strong 
independent predictor of mortality between 30 days and 1 year. The presence of AF, 
especially when MLBCs occurred, was associated with a poor prognosis and high rate of 
mortality. 
Currently, dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and 
clopidogrel for 3 to 6 months is an empirical strategy widely accepted for patients 
undergoing TAVI.12 However, a randomized single-center study could not find any 
benefit in patients treated with DAPT for 3 months post TAVI with regards to the risk of 
cerebrovascular events or major adverse cardiac events compared to ASA monotherapy.13 
Thus, to date the optimal strategy and in particular pharmacological intervention for 
reducing the risk of cerebrovascular events post TAVI is unknown. 
Antithrombotic treatment is believed to be a cornerstone for the prevention of ischemic 
cerebrovascular accidents during and post TAVI. Current recommendations for 
antithrombotic agents and strategies for TAVI are not based on large controlled 
randomized studies.12,13,14,15,16,17 There is an unmet need for improved antithrombotic 
therapies and strategies given the fact that the incidence of major stroke has not declined 
significantly overtime. In PARTNER, heparin was used for procedural anticoagulation 
(5000 bolus loading dose) with a target of activated clotting time >250 s, whereas 
guidelines recommend a target time of 300 s. Similarly, dual antiplatelet therapy 
(loading dose, maintenance dose, duration) after TAVI has not been explicitly defined. 
PARTNER recommendation was 75-100 mg of daily aspirin, a 300 mg clopidogrel 
loading dose and 75 mg once-daily for 6 months following TAVI.14,15 However 
clopidogrel duration or loading dose are not specifically defined in guidelines, and lately 
the general usefulness of clopidogrel on top of aspirin in TAVI patients has been 
questioned.13,16 In two studies comparing DAPT to single-antiplatelet therapy with either 
aspirin or clopidogrel, DAPT did not reduce the incidence of new cerebrovascular 
accidents but was associated with significantly higher rates of major and life-threatening 
bleeding complications.13,17 Since it is unclear whether thrombi produced during and 
after TAVI are of platelet or thrombin based origin, the latter may not favor clopidogrel 
as an effective agent in these patients. 
Controversy also exists for patients with a history of pre-existing atrial fibrillation. No 
consensus or evidence from trials exist regarding treatment with triple therapy, warfarin 
with one antiplatelet, or warfarin alone, although American and Canadian guidelines 
discourage the use of triple therapy.16,18,19 Triple therapy after TAVI should be avoided 
in these patients with a high inherent bleeding risk. Furthermore, data show no difference 


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in stroke rates in single antiplatelet vs. dual antiplatelet therapy, and the combination of 
one oral anticoagulant with one antiplatelet has recently shown better safety results 
without excess ischemic events in comparison to triple therapy in AF patients undergoing 
PCI.17,20 
1.2. 
Study Rationale 
Edoxaban is a globally approved oral anticoagulant that directly and selectively inhibits 
factor Xa. Factor Xa initiates the final common pathway of the coagulation cascade 
inducing the formation of thrombin, which catalyzes additional coagulation-related 
reactions and promotes platelet activation. Novel anticoagulants such as Edoxaban may 
have the potential to directly inhibit the TAVI-related thrombogenicity in the early period 
and at the same time significantly reduce the incidence of bleeding events in patients on 
standard (Vitamin K antagonist [VKA]) oral anticoagulation. 
1.2.1. 
Dose Rationale 
Based on the results of the ENGAGE AF-TIMI 4821 and Hokusai22 studies, an Edoxaban 
dose that is considered 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 TAVI but 
no additional evidence exists suggesting further dose adaptation. 
The doses selected for VKA are those that have been found to be effective in patients 
with AF. 
 
1.3. 
Risks and Benefits for Study Subjects 
Subjects with AF undergoing PCI with stent placement require the use of oral 
anticoagulants (OACs) with single or dual antiplatelet therapy (i.e., a P2Y12 antagonist 
and acetylsalicylic acid) to reduce the risk of stroke, systemic embolic event (SEE), stent 
thrombosis and other myocardial ischemic events, and related cardiovascular morbidity 
and mortality. Whereas the concomitant use of OACs with antiplatelet agents reduces the 
risk of thromboembolic events, such therapy also increases the risk of bleeding. 
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. 
The risks of Edoxaban in patients undergoing TAVI are not known. For a summary of 
known risks for Edoxaban and VKA refer to their locally approved label. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Co-Primary Objectives 
• To assess the effect of Edoxaban versus Vitamin K antagonist (VKA) on net 
adverse clinical events (NACE), i.e., the composite of all-cause death, 
myocardial infarction (MI), ischemic stroke, SEE, valve thrombosis, and 
major bleeding (International Society on Thrombosis and Haemostasis [ISTH] 
definition). 
• To assess the effect of Edoxaban versus VKA on major bleeding (ISTH 
definition). 
 
2.1.2. 
Secondary Objectives 
To compare Edoxaban with VKA with regards to the following efficacy endpoints: 
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, 
valve thrombosis, and major and minor bleeding per Thrombolysis in 
Myocardial Infarction (TIMI) definitions 
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, 
valve thrombosis, and major bleeding (Bleeding Academic Research 
Consortium [BARC] 3 or 5 definition) 
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, 
valve thrombosis, and major and moderate bleeding (Global Utilization of 
Streptokinase and Tissue Plasminogen Activator for Occluded Arteries 
[GUSTO] definition) 
• Major Adverse Cardiac Events (MACE), defined as the composite of all-cause 
death (excluding adjudicated non-cardiac death), MI, or repeat coronary 
revascularization of the target lesion 
• Major Adverse Cardiac and Cerebrovascular Events (MACCE), defined as the 
composite of all-cause death (excluding adjudicated non-cardiac death), MI, 
stroke (ischemic, hemorrhagic, or undetermined), or repeat coronary 
revascularization of the target lesion 
• Cardiovascular mortality 
• Stroke (ischemic, hemorrhagic, or undetermined) 
• Stroke (ischemic) 
• Stroke (hemorrhagic) 
• Stroke (undetermined) 
• Fatal stroke (ischemic, hemorrhagic, or undetermined) 
• Non-fatal stroke (ischemic, hemorrhagic, or undetermined) 


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• SEE 
• Myocardial Infarction 
• Valve thrombosis 
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To compare Edoxaban with VKA with regards to the following safety endpoints: 
• Bleeding defined as TIMI major or minor, BARC 3 or 5, and GUSTO 
moderate or severe 
• Bleeding defined as ISTH major and Clinically Relevant Non-Major 
(CRNM); TIMI major/minor bleeds or requiring medical attention; BARC 2, 
3, or 5; and GUSTO moderate or severe 
• Bleeding defined as ISTH CRNM, TIMI minor or requiring medical attention, 
BARC 2, and GUSTO moderate 
• All bleeding that are not ISTH major, CRNM; TIMI minimal; BARC 1 non- 
actionable; and GUSTO mild 
• Any bleeding 
• Intracranial hemorrhage 
• Life-threatening bleeding 
• Fatal bleeding (fulfilling the ISTH major bleeding definition) 
• Non-fatal major bleeding (ISTH definition) 
• All-cause mortality 
• Cardiovascular mortality 
• Safety parameters such as (serious) adverse events ([S]AEs), laboratory 
parameters, electrocardiogram (ECG), and vital signs 
 
2.1.3. 
Other objectives: 
To compare Edoxaban with VKA with regards to the following: 
• Number of hospital admissions, defined as ≥ 24 h stay in the hospital, due to 
cardiovascular causes (post TAVI and non-TAVI procedure related), including 
but not limited to overall, for bleeding, SEE, venous thrombosis, shock, 
arrhythmia, cardiac rupture, stroke, aneurysms, stent occlusions, etc. 
o Hospital admissions due to cardiovascular causes include, but are not 
limited to the Emergency Department (ED), Intensive Care Unit 
(ICU), and cardiovascular ward. 
• Treatment satisfaction as assessed by the Perception Anticoagulant Treatment 
Questionnaire (PACT-Q) 
• Health related quality of life as assessed by the Euro Quality of Life (EQ-5D- 
5L) Questionnaire 


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• Optional: Sub-studies not interfering with the main study may be added 
including such as the assessment of biomarkers of hemostasis/coagulation and 
of cardiovascular risk such as but not limited to whole blood clotting time 
(WBCT), thromboelastography (TEG), and multiple electrode aggregometry 
(MEA), high sensitivity-troponin T (Hs-TnT), growth differentiation factor-15 
(GDF-15), cystatin-C. 
 
2.2. 
Study Hypothesis 
There are 4 primary hypotheses that will be tested in hierarchical order: 
• Hypothesis (1): 
o The Edoxaban-based regimen is noninferior to the VKA-based regimen 
with regards to NACE. 
• Hypothesis (2): 
o The Edoxaban-based regimen is noninferior to the VKA-based regimen 
with regards to major bleeding (ISTH definition). 
• Hypothesis (3): 
o The Edoxaban-based regimen is superior to the VKA-based regimen with 
regards to major bleeding (ISTH definition). 
• Hypothesis (4): 
o The Edoxaban-based regimen is superior to the VKA-based regimen with 
regards to NACE. 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
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This is a multinational, multicenter, prospective, randomized, open-label study with 
blinded evaluation of endpoints (PROBE) parallel group study comparing Edoxaban 
with VKA in subjects with AF having undergone TAVI. Critical events will be 
adjudicated by an independent Clinical Events Committee (CEC). An independent Data 
and Safety Monitoring Board (DSMB) is responsible for monitoring safety during the 
study. 
Following signing of written informed consent, subjects are screened for eligibility and 
may be randomized the evening of the day of TAVI to 5* days, i.e., until 23:59 of the 
5th* day after the successful TAVI (see inclusion criteria #1 for definition of 
“successful”) and the subject is qualified based on all the protocol defined 
inclusion/exclusion criteria. The first dose of OAC should be administered within the 
5 days after TAVI (in case of pacemaker deployment within the 7 days after TAVI) but 
must be administered within 24 hours post randomization; however, NO EARLIER than 
the morning after successful TAVI. 
*If subject is waiting on a decision on pacemaker surgery, then can extend to 7 (7th) days 
o Subjects eligible to participate in the study will be randomized via 
interactive web/voice response system (IXRS) such that the study will 
have a 1:1 ratio of subjects in the following study arms (Figure 3.1). 
Edoxaban 60 mg once-daily or 30 mg once-daily in subjects meeting dose 
reduction criteria according to the locally approved label. 
• Edoxaban-based regimen: 
o Edoxaban 60 mg once-daily or 30 mg once-daily in subjects meeting the 
dose reduction criteria per the locally approved label. 
• VKA-based regimen: 
o The VKA of choice (any locally approved), dose-adjusted throughout the 
study to achieve an international normalized ratio (INR) of 2.0 to 3.0 
(numbers inclusive) [Japan: 1.6 to 2.6 in subjects aged ≥70 (numbers 
inclusive)]. 
In addition to the above described oral anticoagulation therapy, antiplatelet management 
in this study shall follow the scenarios as outlined below: 
• Subjects having undergone TAVI without other potential indications for 
antiplatelet therapy (APT) may obtain either no APT or single APT (SAPT) up to 
90 days; i.e., ASA or P2Y12 inhibitor (preferably clopidogrel). 
• Subjects having undergone TAVI with PCI either prior to or during the study 
period may obtain SAPT indefinitely, i.e., any P2Y12 inhibitor (preferably 
clopidogrel) or ASA. DAPT is only allowed post stenting for up to 3 months 
after PCI. 


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• Subjects having undergone TAVI with other potential indications for oral 
antiplatelet therapy may obtain either no APT or SAPT, i.e., any P2Y12 inhibitor 
(preferably clopidogrel) or ASA indefinitely. 
 
The type (i.e., the international nonproprietary name, the dose, and the projected 
last dose of all antiplatelet agents) must be predeclared at randomization. ASA 75- 
100 mg/day or generic/branded clopidogrel 75 mg/day (chronic therapy following 
loading dose) are the preferred agents. Type, dose, and (projected) last dose may be 
changed during the treatment period for documented medical reasons. 
Figure 3.1: 
ENVISAGE-TAVI AF Study Design 
 
*If subject is waiting on a decision on pacemaker surgery, then can extend randomization to 7 (7th) days 
NOTE: While it is required to administer the first dose of OAC within 24 h post randomization, this dose is 
NOT to be administered earlier than the morning after successful TAVI. 
 
3.2. 
Discussion of Study Design 
This study is designed to statistically compare net adverse clinical events of an 
Edoxaban-based antithrombotic regimen with a VKA-based antithrombotic regimen in 
non-valvular AF subjects after successful TAVI. At present (2017) there are only limited 
data and no consensus among experts on how to best treat subject with non-valvular AF 
following successful TAVI procedures. Hence, medical societies differ in their treatment 
recommendations as well.12,13,15,16,17 The current understanding is that antithrombotic 
therapy is needed using antiplatelet agents for three months and lifelong oral 
anticoagulants in AF subjects. However, there is a debate on the best timing of the use of 
antiplatelet agents and oral anticoagulants in such a setting. The situation becomes even 
more complex in patients with non-valvular AF who either received a stent within the last 
few months before TAVI or will be subject to stenting after aortic valve replacement as 
stenting triggers oral antiplatelet therapy for up to 12 months. This scenario applies to at 


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least 25-34% of the TAVI patients.23,24,25 Though single antiplatelet therapy is the 
preferred strategy in the majority of these cases, dual antiplatelet therapy may be 
warranted for a shorter period of time in patients at high risk for stent thrombosis. 
The design of ENVISAGE-TAVI AF accounts for all of these options. 


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4. 
STUDY POPULATION 
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Subjects must sign and date the informed consent form provided by the study center 
before any study-specific qualification procedures are conducted. While successful 
TAVI is a required inclusion criterion, the TAVI procedure is not part of this study; 
however, information derived from the procedure will be documented and used for 
analysis of this study. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Successful TAVI via transvascular access routes such as the femoral, carotid, 
axillary, and subclavian arteries. Other access routes need prior approval per a 
majority vote from 3 members of the Executive Committee (both Global Lead 
Investigators and the Daiichi Sankyo Medical Lead or his/her designee). Success 
is defined as: 
a. Correct positioning of a single prosthetic heart valve into the proper 
anatomical location 
b. Presence of all 3 conditions post TAVI 
i. Mean aortic valve gradient <20 mmHg 
ii. Peak transvalvular velocity <3.0 m/s 
iii. Aortic valve regurgitation of 2 or less 
c. No clinically overt stroke 
d. No uncontrolled bleeding at time of randomization 
2. Indication for chronic OAC 
a) Documented pre-existing AF 
b) New onset AF (e.g., > 30 seconds documented by ECG) 
3. Provision of signed informed consent 
4. Age ≥18 years 
 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the 
study: 
 
4.2.1. 
Bleeding risks or systemic conditions 
1. Conditions with a high risk of bleeding 
o This may include but is not limited to: active peptic ulcer with upper 
gastrointestinal bleeding within last 90 days prior to randomization, 
malignancy at high risk of bleeding, major intraspinal or intracerebral 
vascular abnormalities, recent unresolved brain or spinal injury, or spinal 
surgery (recent = within the last 90 days prior to randomization), any 


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intracranial hemorrhage, known or suspected esophageal varices, 
arteriovenous malformations, or clinically relevant vascular aneurysms 
2. Other known bleeding diatheses 
3. Conditions that make it difficult for the subject to swallow the study medication 
 
4.2.2. 
Procedure related 
4. Serious unresolved periprocedural complications 
 
4.2.3. 
Medication related 
5. Any contraindication to EITHER Edoxaban OR VKA per local label; this 
includes hypersensitivity to the active ingredient, or to any of the excipients, or 
any of the components of the study medications 
6. Concomitant treatment with other antithrombotic agents, ASA > 100 mg/day, 
fibrinolytic therapy, or chronic (> 4 days/week) use of nonsteroidal anti- 
inflammatory drugs (NSAIDs); however, NSAID patches are permitted 
7. Requirement for DAPT at randomization that will be indicated for more than 3 
months beyond the first study dose of OAC 
8. Treatment with other investigational (i.e., non-approved) drugs or devices within 
30 days before enrollment or planned use of investigational drugs or devices 
during the study 
 
4.2.4. 
Concomitant conditions and therapies 
9. Clinically overt stroke within the last 90 days before TAVI 
10. Any scheduled drug or device-based therapy during the treatment period that 
would eliminate the need for chronic oral anticoagulation (any other diagnostic or 
therapeutic procedure that is associated with temporary interruption of OAC is 
permitted) 
11. (former exclusion criteria 11 is no longer applicable, numbers not adjusted to 
keep alignment with version 2.0 of the protocol) 
12. Any bail out catheter based cardiac interventional procedure during the index 
TAVI (however, during the same session as TAVI (pre or post TAVI) scheduled 
PCI and angioplasty of the iliac/femoral arteries are permitted) 
13. Subjects with mechanical heart valves 
14. Mitral valve stenosis Grade III-IV/IV (moderate to severe/severe); however, 
subjects with moderate mitral valve stenosis may be enrolled into the study 
15. Active infective endocarditis 
16. Major surgery within 30 days prior to randomization 
17. (former exclusion criteria 17 is no longer applicable, numbers not adjusted to 
keep alignment with version 2.0 of the protocol) 
18. ST-elevation myocardial infarction within 30 days prior to TAVI until 
randomization (non-ST-elevation myocardial infarction is no exclusion) 


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19. End stage renal disease (creatinine clearance [CrCL] < 15 mL/min or dialysis) at 
randomization 
20. Severe hepatic impairment or hepatic disease associated with coagulopathy (e.g., 
acute/chronic active hepatitis or cirrhosis, Child Pugh B, C) 
21. Uncontrolled severe hypertension documented by repeated BP ≥170/100 mmHg, 
despite medical intervention 
22. Respiratory failure requiring mechanical ventilation at time of randomization 
23. Critically ill or hemodynamically unstable subjects at the time of randomization, 
i.e., cardiogenic shock, acute heart failure, including the requirement for 
pharmacologic treatment or mechanical support to assist circulation 
24. Active malignancy (requiring chemotherapy, radiation or surgery at the time of 
randomization) except for adequately treated non-melanoma skin cancer or other 
noninvasive or in situ neoplasms (e.g., cervical cancer in situ that has been 
successfully treated); anti-hormonal therapy is allowed 
 
4.2.5. 
Other exclusion criteria 
25. Any of the following abnormal local laboratory results at the time of 
randomization: 
o Platelet count < 50 x 109/L 
o Hemoglobin < 8 g/dL (5 mmol/L at randomization, no ongoing bleeding, 
no transfusion of whole blood or red blood cells within 24 hours); 
however, for subjects with a history of hemoglobin of no less than 
7.5 g/dL while under chronic OAC, the exclusion will be based on 
hemoglobin of <7.5 g/dL 
26. Female subjects of childbearing potential without using highly effective methods 
of contraception (i.e., a method of contraception with a failure rate < 1% during 
the course of the study, including the follow-up period). A female of childbearing 
potential is defined as one who has not been postmenopausal for at least one year, 
or has not been surgically sterilized, or has not had a hysterectomy at least three 
months prior to the start of this study [Visit 1]). Females taking oral 
contraceptives should have been on that therapy for at least three months. Highly 
effective methods of contraception includes 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; along with barrier methods of contraception 
(male condom, female condom, cervical cap, diaphragm, contraceptive sponge). 
27. Pregnant or breast-feeding subjects 
28. Assessment by the Investigator that the subject is not likely to comply with the 
study procedures or will complete follow-up 
29. Current participation in another clinical trial (unless the registry DOES NOT 
interfere with the evaluation of ENVISAGE-TAVI-AF as per this protocol. 


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Before including such a subject, the Investigator should discuss the situation with 
the Daiichi Sankyo Medical Lead or his/her designee) 
30. Previous randomization in this study 
31. Drug or alcohol dependence within the past 12 months prior to randomization as 
judged by the Investigator 
32. Life expectancy less than 6 months beyond the targeted last visit 
33. Subjects with antiphospholipid syndrome who are triple positive (for lupus 
anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I 
antibodies) with thrombosis 


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5. 
STUDY TREATMENT(S) 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s) 
Following the signing of written informed consent, subjects are screened for eligibility 
and may be randomized the evening of the day of TAVI to 5* days, i.e., until 23:59 of the 
5th* day after the successful TAVI (see inclusion criteria #1 for definition of “successful”) 
and the subject is qualified based on all the protocol defined inclusion/exclusion criteria. 
The first dose of OAC should be administered within the 5 days after TAVI (in case of 
pacemaker deployment within the 7days after TAVI) but must be administered within 24 
hours post randomization; however, NO EARLIER than the morning after successful 
TAVI. Low-dose aspirin treatment (75-100 mg/day) or approved other P2Y12 antagonist, 
preferably clopidogrel (75 mg/day), will be prescribed as per Investigator discretion. 
This needs to be pre-declared prior to randomization. Treatment duration will be as per 
the protocol for up to 36 months (with a minimum of 6 months for last subject 
enrolled) unless the subject reaches a primary endpoint. However, the subject will 
continue to be followed until the end of the study (i.e., this may be longer than to end of 
treatment). 
*If subject is waiting on a decision on pacemaker surgery, then can extend to 7 (7th) days 
Treatment arms include: 
• Treatment arm 1 [Experimental]: Edoxaban – 60 mg once-daily or 30 mg 
once-daily in subjects meeting the dose reduction criteria per the locally 
approved label. 
• Treatment arm 2 [Control]: VKA – The oral VKA of choice (any locally 
approved) dose-adjusted throughout the study to obtain an INR of 2.0 to 3.0 
(numbers inclusive) [Japan: 1.6 to 2.6 in subjects aged ≥70 (numbers 
inclusive)]. 
In addition to the above described oral anticoagulation therapy, antiplatelet 
management in this study shall follow the scenarios as outlined below: 
o Subjects having undergone TAVI without other potential indications for 
APT may obtain either no APT or SAPT up to 90 days, i.e., ASA or a 
P2Y12 inhibitor (preferably clopidogrel). 
o Subjects having undergone TAVI with PCI either prior to or during the 
study period may obtain SAPT indefinitely, i.e., any P2Y12 inhibitor 
(preferably clopidogrel) or ASA. Dual antiplatelet therapy (DAPT) is 
only allowed post stenting for up to 3 months after each PCI during the 
study period. 
o Subjects having undergone TAVI with other potential indications for oral 
antiplatelet therapy may obtain either no APT or SAPT, i.e., any P2Y12 
inhibitor (preferably clopidogrel) or ASA indefinitely. 


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Protocol DU176B-C-U4001 
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The type (i.e., the international nonproprietary name, the dose, and the projected 
last dose of all antiplatelet agents) must be predeclared at randomization. ASA 75- 
100 mg/day or generic/branded clopidogrel 75 mg/day (chronic therapy following 
loading dose) are the preferred agents. Type, dose, and (projected) last dose may be 
changed during the treatment period for documented medical reasons. 
5.1.2. 
Method of Treatment Allocation 
Prior to randomization of a subject, all eligibility criteria must be met and a signed 
informed consent obtained. 
Enrollment and randomization must occur between the evening of the day of TAVI and 
5* days, i.e., until 23:59 of the 5th* day provided that the TAVI procedure has been 
judged as successful (See inclusion criteria #1 for definition of successful TAVI) and the 
subject is qualified based on all the protocol defined inclusion/exclusion criteria. All 
sites will be required to maintain a record of all subjects screened for the trial. The 
reason for screen failure must be documented in the subject’s records. Subjects must be 
randomized without delay and administered their first dose of study medication within 
24 hours post randomization; however, NO EARLIER than the morning after successful 
TAVI. Randomization will be performed using the IXRS system for subjects meeting all 
eligibility criteria. The directions on how to use the system will be provided in the IXRS 
Quick Reference Manual. The randomization scheme will be securely stored at the 
statistical department of the database management center. 
*If subject is waiting on a decision on pacemaker surgery, then can extend to 7 (7th) days 
Based on this information, the system will assign a unique subject identification number 
and treatment for that subject. Trial randomization will not be blinded and once subject 
is assigned to a treatment arm, no treatment cross-over is permitted. Subjects will be 
randomly assigned in a 1:1 ratio to receive Edoxaban or VKA. The Investigator will 
pre-declare the type (if any) P2Y12 antagonist or ASA treatment and its projected last 
dose prior to the randomization (pre-declaration, via the IXRS). 
The Investigator’s knowledge of the treatment must not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled. 
 
5.1.3. 
Blinding 
This study is open-label. 
 
5.2. 
Study Drug(s) 
5.2.1. 
Description 
The primary medications within this study are Edoxaban and VKA, referred to as study 
medications. The oral antiplatelet (OAP) co-administered medications for the purpose of 
this protocol are not referred to as study medications, but are within the term study drugs. 
The costs of OAP and VKA for this study will be reimbursed. 






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5.2.1.2.1. Transitioning to Study VKA at Randomization 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
For subjects randomized to VKA, who require switching from any other anticoagulant 
i.e., another VKA, other non-VKA OAC, 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. 
 
Table 5.3: 
Transitioning to Study VKA at Randomization 
 
INR = international normalized ratio; NOAC = non- oral anticoagulant(s); OAC = oral anticoagulant(s); 
VKA = vitamin K antagonist 
 
5.2.1.2.2. Transitioning from Study VKA at EOT 
Table 5.4: Transitioning from Study VKA at EOT 
 
INR = international normalized ratio; OAC = Oral anticoagulant(s); VKA = vitamin K antagonist 


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5.2.1.3. 
P2Y12 antagonist: 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
Clopidogrel (generic/branded) 75 mg, commercially/locally available tablets for once- 
daily oral use is the preferred P2Y12 antagonist for this study. 
 
5.2.1.4. 
Acetylsalicylic acid (ASA): 
ASA 75-100 mg once-daily for oral use. 
 
5.2.2. 
Supply of Medications 
Sponsor supplies participating sites with Edoxaban, consisting of 60 mg and 30 mg film- 
coated tablets. The Sponsor will also supply transition kits containing Edoxaban 30 mg 
and 15 mg to be used for subjects transitioning from Edoxaban to VKA. 
Sites or treating physicians will provide or prescribe VKA, clopidogrel, and ASA as per 
local standard of care guidelines and as specified in the protocol. Please refer to the 
locally approved label for the summary of product characteristics (SmPC) of each study 
medication and co-administered medication. 
All dosage adjustments for Edoxaban are implemented through the IXRS system at the 
time of the subject’s study visits. For subjects randomized to Edoxaban treatment, the 
IXRS system provides the appropriate Edoxaban supply kit number based on the subject’s 
information as provided by the Investigator. 
 
5.2.3. 
cLabeling and Packaging 
Edoxaban (DU-176b) will be supplied as tablets (60 mg and 30 mg strengths) packaged 
in bottles of 60 tablets in each bottle. Two bottles will be supplied to cover the 3 month 
treatment periods and 4 bottles for the 6 month treatment periods. Edoxaban (DU-176b) 
will be supplied as 15 mg tablets for end of treatment transition at end of treatment. The 
transition supply will consist of Edoxaban 30 mg tablets or 15 mg tablets packaged in 
bottles of 15 tablets each. Protocol-specific packaging and labeling will be completed 
following Good Manufacturing Principles (GMP). 
Subjects will obtain their standard of care medications (e.g., VKA, clopidogrel, and 
ASA), excluding Edoxaban, either from the site or via prescription from the hospital or 
treating physician. 
 
5.2.4. 
Preparation 
There is no special preparation for either Edoxaban tablets or VKA. 
 
5.2.5. 
Administration 
For Edoxaban will be dosed as per IXRS. VKA administration will be based on locally 
approved label instructions. For subjects on VKA, VKA administration should be at 
doses that will to obtain/maintain an INR of 2.0 to 3.0 (numbers inclusive) [Japan: 1.6 to 
2.6 in subjects aged ≥70 (numbers inclusive)]. 


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5.2.6. 
Storage 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
Edoxaban tablets must be stored by the site at 20°to 25°C (68° to 77°F) as measured by a 
thermometer in a secure, limited access storage area. Temperature measurements will be 
recorded on a temperature log excluding weekends and holidays. 
Excursions from 15°to 30°C (59° to 86°F) are permitted. The Sponsor/contract research 
organization (CRO) must be contacted in the event of a temperature excursion outside 
this range. 
Other medications must be stored as per labeled storage conditions. 
Upon receipt of shipment, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration 
date, confirm temperature monitor readings, and sign the Receipt of Shipment Form 
provided and file the latter in the site binder. The Investigator or designee will contact 
the IXRS to acknowledge receipt of shipment. In addition, the Investigator or designee 
shall contact Sponsor/CRO as soon as possible if there is a problem with the shipment 
and quarantine the shipment until resolution is obtained from the Sponsor. 
5.2.7. 
Edoxaban Accountability 
The IXRS will contain a Drug Accountability Module for any medications provided by 
the Sponsor (i.e., Edoxaban). The Investigator or designee will enter the required 
information (see IXRS Quick Reference Manual) in the IXRS drug accountability 
module. In addition, the Investigator or designee shall contact Sponsor as soon as 
possible if there is a problem with the shipment. A drug accountability record will be 
provided for Edoxaban. The record must be kept current and should contain the dates 
and quantities of Edoxaban received, subject’s identification number or supply number as 
applicable, for whom the Edoxaban was dispensed, the date and quantity of Edoxaban 
dispensed and remaining, as well as the initials of the dispenser. 
At the end of the study or as directed, all Edoxaban, including unused, partially used, or 
empty bottles, will be returned to the Sponsor, a designee, or destroyed at the site 
according to the site’s drug handling and disposition standard operating procedures 
(SOPs). A copy of these SOPs must be available onsite. The certificate of destruction 
must be provided to Daiichi Sankyo documenting the drug, the quantity (in tablets), 
method of destruction, and date of destruction. 
If sites are unable to destroy drug, the monitor will make arrangements to return drug to a 
designated depot for destruction. 
Medications provided by the Sponsor will be destroyed (or returned) only after the study 
monitor has completed an inventory to verify the quantity to be destroyed (or 
returned). The destruction (or return) of medications provided by the Sponsor must be 
documented and the documentation filed (and if returned, included in the shipment). 
All investigational product inventory forms must be made available for inspection by a 
Sponsor authorized representative or designee and regulatory agency inspectors. The 
Investigator is responsible for the accountability of all used and unused study supplies at 
the site. 


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5.3. 
Control Treatment 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
Sites and or treating physicians will provide or prescribe VKA, clopidogrel, and ASA as 
per local standard of care guidelines and as specified within the protocol. 
 
5.4. 
Dose Reductions 
Dose reduction for Edoxaban or VKA will be based on the country-specific approved 
label precautions and recommendations. 
 
5.5. 
Method of Assessing Treatment Compliance 
The first dose of randomized study medication regimen is administered under nursing 
supervision. Each subject should document missed doses and Investigator captures 
information in the eCRF. 
As per Table 17.1, the Investigator or designee assesses the subject’s compliance with the 
assigned regimen which may include the subject’s memory aid; however, dosing 
compliance will be primarily by: 
• Dosing compliance for Edoxaban will be assessed by means of tablet/bottle 
counts remaining or bottles returned. All Edoxaban packaging will be returned at 
each subject visit; an accounting of tablets will be made and recorded in the 
eCRF. If zero tablets/bottles returned, ask subject whether any were 
disposed/thrown away, rather than taken orally, and this information will be 
recorded in the eCRF. 
• Dosing compliance for VKA will be assessed by time within the therapeutic range 
of an INR from 2.0 to 3.0 (numbers inclusive) [Japan: 1.6 to 2.6 in subjects aged 
≥70 (numbers inclusive)]. INR values will be entered into the eCRF. 
• Dosing compliance to any other co-administered medications, (i.e., oral 
antiplatelets) will also be assessed by following prescriptions and subject 
interview. The information will be recorded in the eCRF. 
All information on compliance with medications will be entered into the eCRF. 
 
5.6. 
Prior and Concomitant Medications 
Pre-specified medications that the subject has taken within 30 days before randomization 
will be recorded in the “targeted concomitant medications” eCRF. Subjects who were or 
are being treated with oral and/or parenteral anticoagulants are eligible for the study only 
if from the time of randomization these drugs can be replaced by another oral 
anticoagulant. These pre-specified medications taken by the subjects upon entry to the 
study or at any time during the study are regarded as targeted concomitant medications 
and must be documented on the appropriate pages of the eCRF. If the subject 
experiences an endpoint event or an SAE, then information on targeted and non-targeted 
concomitant medications taken within the past 30 days prior to the SAE through to the 
resolution of the SAE must be documented on the appropriate eCRF pages. Concomitant 
therapy will be captured through the subject’s Post-treatment Follow-up Visit, or in the 


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Protocol DU176B-C-U4001 
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case of an SAE reported between that visit and the end of the study, see previous 
sentence. 
With the exception of where the Investigator has pre-declared antiplatelet therapy, there 
are no other concomitant medications required as part of the study design. 
 
5.7. 
Prohibited Medications 
The following drugs and devices MUST NOT be used during the treatment period unless 
no alternative therapy is clinically suitable. 
• Anticoagulants, other than the assigned study medication, by any route with the 
exception of parenteral agents used as a bridge when starting or resuming study 
drug as per approved local label for subject’s study drug; 
• Fibrinolytic agents, if required to treat acute MI or pulmonary embolism (PE), 
require study medication interruption and consideration of a transfusion of fresh 
frozen plasma; 
• Dual antiplatelet therapy is prohibited while on study medication except for rare 
occasions such as for 3 months post coronary stenting (Section 3.1, post TAVI 
stenting). Examples of dual antiplatelet therapy include aspirin plus a P2Y12 
antagonist such as clopidogrel. Single antiplatelet therapy with any antiplatelet 
agent is permitted as described throughout this protocol. 
• Chronic use of NSAIDs including both cyclooxygenase-1 (COX-1) and 
cyclooxygenase-2 (COX-2) inhibitors other than aspirin for >4 days/week; 
• The use of P-glycoprotein (P-gp) inhibitors during this study shall be in 
accordance with the approved local label for the subject’s study medication 
except as listed below. 
• Systemic use of P-gp inhibitors such as ketoconazole, itraconazole, 
erythromycin, and clarithromycin may require adjustment of study medication 
based on the approved local label for the subject’s study medication. P-gp 
inhibitors are generally prescribed for short-term use (≤3 weeks). When 
required use of P-gp inhibitors necessitates the temporary interruption of study 
medication, or dose reduction for the study drug Edoxaban, the subject should 
restart study medication after completing treatment with the P-gp inhibitor. 
Topical use of these medications is allowed while taking study medication. 
• Other investigational drugs or devices. 
The Investigator is encouraged to contact CRO medical monitor if he/she would like to 
discuss concomitant medications for a particular subject. 
If a subject can safely stop the prohibited concomitant medication (e.g., two-week course 
of ketoconazole, etc.), then study medication can and should be resumed according to 
approved local label (usually the day after the last dose of the prohibited concomitant 
medication). Regardless of the duration of study medication interruption, once the 
prohibited concomitant medication is stopped, study medication may be resumed. 


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Protocol DU176B-C-U4001 
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Information regarding concomitant medications will be collected with start date, stop 
date, drug name, dose and dosing regimen. 
If required as part of standard of care, a reversal agent may be used in accordance with 
locally approved label. 
 
5.8. 
Subject Withdrawal/Discontinuation 
The intended duration of the two treatment regimens is up to 36 months. Subjects must 
stay on the assigned OAC-based regimen as much as possible. 
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 
(Section 17.7), 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 over diuresis 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 dose 
decreased 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 the subject refuses continuation of 
any medication in the assigned study regimens. 
All subjects are followed through to the termination of the study irrespective of changes 
in the antithrombotic regimen. Clinical follow-up before the end of the study is only 
terminated at the explicit documented request of the subject or his/her death. 
All study drug start and stop dates are captured in eCRF together with the reason for 
interruption or discontinuation. 
 
5.8.1. 
Reasons for Study Drug Interruption/Discontinuation 
Any reason for study drug interruption/discontinuation will be recorded in the eCRF. 
Such reasons include, but are not limited to the following: 


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• Reasons Related to AE: 
Protocol DU176B-C-U4001 
Version 4.0, 29 Jul 2019 
o Initiating or continuing study drug would place the subject at undue 
hazard as determined by the Investigator: in particular treatment 
failure or events, e.g., thrombosis, related to non-compliance with the 
anticoagulant regimen 
o When subjects reach a primary endpoint or a key safety endpoint, the 
treating physician needs to decide if OAC medication will be 
permanently discontinued, interrupted, modified or continued. In case 
of intracranial bleeding the protocol mandates stopping the study 
treatment. 
o SAE or other safety concern that is related to study drug treatment; 
o Concurrent increase in aspartate transaminase (AST)/alanine 
transaminase (ALT) > 3 X upper limit of normal (ULN) and bilirubin 
> 2 X ULN in the absence of a known cause (e.g., viral hepatitis, 
cholelithiasis) and where a causal relationship cannot be ruled out; 
o Major life-threatening bleeding (as defined in the CEC Charter, also 
see Section 17); 
o CrCL decreased to <15 mL/min, confirmed by repeat testing at least 
one week later, or need for renal dialysis. 
• Death; 
• Withdrawal of Informed Consent; 
• Lost to Follow-up (every attempt will be made by the Investigator to avoid 
having subjects “lost to follow-up”); 
• Pregnancy; 
• Termination of all or part of the study by the Study Oversight Committee 
acting in concert with the DSMB and the Sponsor. 
• Post randomization changes (other than CrCL decreased to <15 mL/min or 
need for renal dialysis) in health status related to study exclusion criteria 
should not automatically lead to study drug interruption or discontinuation 
unless continuing study drug places the subject at undue hazard as determined 
by the Investigator. Such situations should be handled on a case-by-case 
basis. The Investigator should consult with the CRO medical monitor if a 
subject has a post randomization change in health status that puts the subject 
into an exclusion criterion. 
Those subjects who discontinue study participation after the initiation of study 
medication will have study procedures terminated at the time of discontinuation from 
study with the EOT Visit (Section 6.5).  If the subject discontinued study treatment due to 
an AE, the Investigator will follow the subject until the AE has resolved or stabilized. 
 
5.8.2. 
Subjects with Study Drug Interruptions/Discontinuations 
The Investigator should call the CRO medical monitor in case of any questions regarding 
how to handle a study medication interruption and/or discontinuation. 


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Protocol DU176B-C-U4001 
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Suspension/Interruption: The date/time of the last dose, the reason for the interruption, 
and other required details will be recorded in the eCRF. Reasons for interruption include 
but are not limited to: development of clinical contraindications for any study drug 
(according to the label of the respective drug). During each interruption of anticoagulant 
or antiplatelet therapy, subjects are evaluated to determine whether the subject can safely 
resume the study drug. 
Discontinuation: The date/time of the last dose, the reason for the discontinuation, and 
other required details will be recorded in the eCRF. For some potential reasons for 
discontinuation of study drug see Section 5.8.1 and locally approved drug label. 
During a study drug interruption or after study drug discontinuation, a subject can be 
placed on another antithrombotic therapy per local guidelines and Investigator discretion. 
All randomized subjects, including those who discontinued study medication, will be 
followed through the overall end of the study for the primary and secondary efficacy and 
safety endpoints and SAEs. If the subject has an onsite visit, it is expected that vital signs 
will be obtained along with any laboratory assessments deemed appropriate by the 
Investigator. 
If a subject who discontinues study drug also withdraws consent, in writing, for 
participation in the study, the protocol-specified consent withdrawal procedures 
(Section 5.8.3) must be completed. 
If the subject interrupts (or discontinues) study drug due to an AE, the Investigator will 
follow the event until it has resolved or stabilized. 
 
5.8.3. 
Withdrawal of Consent from Study Participation 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject 
has the right to withdraw consent for participation in the study at any time and for any 
reason without prejudice to his/her future medical care by the physician or at the 
institution. 
If a subject withdraws consent to participate in the study, the Investigator will complete 
and report the observations as thoroughly as possible up to the date of consent withdrawal 
and including the date of the final dose of study medication. The Investigator will clearly 
document the reason for consent withdrawal in the medical record and will complete the 
associated eCRF. Under no circumstances will a subject have to undergo any study visit 
if he/she has expressed the will to leave the study; however, every attempt should be 
made to have the subject complete the 30-day Follow-up Visit (Section 6.6), be followed 
until the end of the study for study endpoints and SAEs (Section 6.7), and provide the 
subject with the information needed for transition to standard of care VKA 
(Section 6.5.1). If this is not possible, the subject will be offered the opportunity to 
consent to one of the following: 
• Providing information about his/her own health status by telephone or other 
means until the 30 days post last dose, 
• Allowing the query of their medical records, 
• Allowing the use of public databases to determine subject status until the end of 
the study. 


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5.8.4. 
Subject Replacement 
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Version 4.0, 29 Jul 2019 
As an endpoint study with enrollment continuing until the required number of adjudicated 
events are reached, there is no need to formally replace a subject. 
 
5.8.5. 
Subject Re-screening Procedures 
There will be no re-screening of subjects for this study. 


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6. 
STUDY PROCEDURES 
6.1. 
Screening Visit 
Protocol DU176B-C-U4001 
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From 12 hours to 5* days, i.e., until 23:59 of the 5th* day after the successful TAVI and 
prior to randomization, all screening procedures will be completed. See Table 17.1 for a 
listing of all screening procedures. 
The following activities will be performed 12 hours and 5* days, i.e., until 23:59 of the 
5th* day after the successful TAVI (See inclusion criteria #1 for definition of successful 
TAVI), prior to randomization and after obtainment of written informed consent 
(no screening procedures may be performed unless written informed consent has 
been obtained): 
*If subject is waiting on a decision on pacemaker surgery, then can extend to 7 (7th) days 
The informed consent form (ICF) must be signed by the subject before any study-specific 
procedure including randomization. A Screening eCRF must be completed for every 
subject with a signed ICF. Any protocol-specified study qualification procedures/tests 
not already done as part of routine care will need to be conducted after the ICF has been 
signed and before randomization. 
• Enter subject into IXRS 
• Check the most recent results from local laboratory tests done within the 15 days 
prior to randomization against the inclusion/exclusion criteria. Creatinine and 
complete blood count (CBC) must be available from blood draws after TAVI with 
the subject being clinically stable. CrCL should be calculated by the Cockcroft- 
Gault formula as described in Section 17.7. For subjects already on a VKA, 
review and record most recent INR results 
• Record demographic information (date of birth/age, sex, ethnicity, and race) 
• Record medical / surgical history (including bleeding history) 
• Eligibility evaluation (inclusion and exclusion criteria). No subject may be 
randomized unless all eligibility criteria are met. 
• Serum pregnancy test for female subjects who are of childbearing potential. 
6.2. 
Randomization Visit (Day 1) 
Randomization must take place within the evening of the day of TAVI and 5* days, i.e., 
until 23:59 of the 5th* day provided that the TAVI procedure has been judged as 
successful (See inclusion criteria #1 for definition of successful TAVI), and the subject is 
qualified based on all the protocol defined inclusion/exclusion criteria. Randomization 
should occur as soon as possible after signing the informed consent, given eligibility is 
confirmed. 
*If subject is waiting on a decision on pacemaker surgery, then can extend to 7 (7th) days 
• Check subject against inclusion/exclusion criteria including the most recent lab 
results. 
• Record type of TAVI device inserted into subject in the eCRF 


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Protocol DU176B-C-U4001 
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• Enter elements for EuroSCORE 1, EuroSCORE 2, Society of Thoracic Surgeons 
(STS), CHAD, and HAS-Bleed scores into the eCRF 
• Contact IXRS for randomization and pre-declaration of OAP. 
• Prior to any study drug administration or other tests, the subject must complete 
the PACT-Q1 and EuroQoL (EQ-5D-5L) questionnaires. These will be collected 
and uploaded into the data base by the CRO via the eCRF. 
• If ECG was performed as part of routine medical practice, record the results. If 
not obtained as part of routine medical practice, collect a pre-dose ECG for 
baseline measurement and record results. 
• Update medical / surgical history (including bleeding history) since screening 
• Physical Examination including 
o Record vital signs (blood pressure and heart rate after the subject has 
been resting at least 5 minutes in a sitting position; body temperature, 
and weight) 
o Record height 
• Record prior (since screening) medications and review as per exclusion 
criteria. 
• If echocardiogram (transthoracic echo [TTE] or transesophageal echo [TEE]) 
was performed pre-TAVI per local standard of care, the information will be 
recorded as specified in the eCRF. 
• Draw blood for analysis by an accredited/certified local laboratory 
(Section 9.9) (if recent [within the 15 days before randomization] are available 
from standard of care, these values may be used instead of requiring an 
additional blood draw). Creatinine and CBC must be available from blood 
draws after TAVI and the subject must be clinically stable. CrCL should be 
calculated by the Cockcroft-Gault formula as described in Section 17.7 and 
the results need to be available prior to the 1st dose of study drugs for subjects 
randomized to Edoxaban. Include a liver panel only if recent (within the 15 
days before randomization) results are not already available. 
• For childbearing potential female subjects, a urine pregnancy test (e.g., 
dipstick test) will be performed at Randomization, 3 months, 12 months, 
24 months, and End of Treatment Visits. Furthermore, pregnancy tests will be 
carried out whenever there are clinical indications for the existence of a 
pregnancy. 
• First administration of assigned study medication within 24 hours of 
randomization; however, NO EARLIER than the morning after successful 
TAVI. 
• Record date/time of first study medication administration in eCRF 
• Instruct subject on the use of study medication (see Section 3.1) 
• Instruct subject on the use of the memory aid 
• Dispense assigned OAC 


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o Daiichi Sankyo supplies study subjects with Edoxaban. VKA and 
OAP may be supplied by the site or via prescriptions issued either by 
the site or attending physician. See Section 3.1 about OAP 
administration. 
• Assessment and recording of (S)AEs and suspected clinical events will start 
immediately after signed informed consent and continue until 30 days after 
the end of treatment with study medication. 
The randomized treatment strategy is implemented after randomization without any 
undue delay. 
 
6.3. 
Prior to Discharge or Transfer to Another Hospital or Hospital 
Department 
No study-related actions, unless driven by a sudden medical need, are required before a 
subject will be either discharged or transferred to another hospital department or hospital 
such as a rehabilitation clinic; however, discharge date needs to be captured in the eCRF. 
 
6.4. 
Continued Treatment Visits 
For all subjects randomized to VKA, all INR measurement shall be performed by local 
accredited/certified labs at a frequency determined by the subject’s treating physician 
(monthly preferred). Trained and certified subjects may perform INR testing themselves 
using an approved point-of-care device but need to provide the results to the Investigator 
and the results need to be recorded in the eCRF. 
o Dose adjustments in VKA will be made to achieve and maintain an 
INR of 2.0 to 3.0 (numbers inclusive) [Japan: 1.6 to 2.6 in subjects 
aged ≥70 (numbers inclusive)] throughout the study. 
For all subjects, study visits (either as on-site or at the subject’s current place of living, 
must be conducted by the Investigator or their appropriately trained designee) at 
3 months (± 14 days), 6 months (± 14 days), and at 6 month intervals (± 14 days) 
thereafter through the end of the study which may be 36 months or longer (i.e., event 
driven study). 
The following procedures will be performed during study visits: 
• Check and record any changes in concomitant medication 
• Assessment and recording of (S)AEs and suspected clinical events since last visit 
• Assessment of any hospitalization for cardiovascular causes (such as shock, 
arrhythmia, cardiac rupture, stroke, aneurysms, stent occlusions, etc.) or bleeding 
• Record vital signs (blood pressure and heart rate after the subject has been resting 
at least 5 minutes in a sitting position; body temperature and weight) 
• Only if medically necessary, 12-lead ECG and recording of the results 
• For childbearing potential female subjects, a urine pregnancy test (e.g., dipstick 
test) will be performed at 3 months, 12 months, 24 months, and End of Treatment 


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Visits. Furthermore, pregnancy tests will be carried out whenever there are 
clinical indications for the existence of a pregnancy. 
• Blood draw for analysis by an accredited/certified local laboratory for all subjects 
(see Section 9.9) or if results are available from standard of care and are within 
15 days prior to the visit these values may be used instead of requiring an 
additional blood draw. 
o The liver function panel needs to be run at the 6 Month and 12 Month 
Visits and if clinically necessary at other times. 
o In subjects randomized to VKA, obtain the subject’s INR records from 
previous visit(s) through to the current visit and adjust dose as necessary 
to obtain/maintain an INR of 2.0 to 3.0 (numbers inclusive) [Japan: 1.6 to 
2.6 in subjects age ≥70 (numbers inclusive)]. INR measure is only 
mandated if the previous measurement was performed more than 3 months 
prior to this visit or the target INR has been shown difficult to achieve. 
• Record all INR results for subjects on VKA since subject’s last visit in eCRF (if 
not recorded earlier in the eCRF). 
• Review and record study regimen compliance and drug interruptions 
o Collect any unused study medication 
• Dispense Edoxaban and inform subjects that VKA and OAP will be provided or 
prescribed from the study site or treating physician, as needed. If approved by the 
local regulatory authority, site should re-dispense the VKA Patient Prescription 
Aid at each study visit. Review dosing records for all subjects, and VKA and 
APT therapy regime and prescription information. All dosing information should 
be recorded in source on the applicable logs, in EDC, and for Edoxaban only, also 
in IXRS. 
• If echocardiogram (TTE or TEE) has been done at any time as medically 
indicated or as per local standard of care in the individual centers, the results will 
be recorded as specified in the eCRF. 
At Months 3 and either Month 12 or at EOT (whichever comes first): 
• Have the subject complete the PACT-Q2 and EQ-5D-5L questionnaire which will 
be provided separately to the sites. This should be done before other procedures 
are conducted. 
6.5. 
End of Treatment (EOT) Visit 
As an event driven study, the subjects will continue on treatment until the study is 
stopped (the end of the study) due to 320 adjudicated events (from approximately 
2500 subject years) will have been reached, or they permanently discontinue from the 
study (for any reason). Subjects enrolled late in the study may be terminated from the 
study after a minimum of 6 months on treatment. The end-of-treatment (EOT) visit is the 
subject’s last treatment visit independent of whether this is the end of the study or occurs 
at time of their withdrawal or discontinuation for any reason. Subjects will also have a 
Post-treatment Follow-up Visit 30 days (± 7 days) after the EOT Visit. 


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The following procedures will be performed: 
• If EOT is prior to 12 months, have the subject complete the PACT-Q2 
questionnaire and EQ-5D-5L questionnaire; if after 12 months on treatment, this 
is not done as it was captured at 12 months. 
• Check and record any changes in concomitant medication 
• Review and record study regimen compliance and drug interruptions 
• Assessment and recording of (S)AEs and suspected clinical events since last visit 
• Assessment of any hospitalization for cardiovascular causes (such as shock, 
arrhythmia, cardiac rupture, stroke, aneurysms, stent occlusions, etc.) or bleeding 
• Record date/time of final dose of study medication 
• Collect all unused study drug(s) 
• For childbearing potential female subjects, a urine pregnancy test (e.g., dipstick 
test) will be performed. 
• Draw blood for analysis by an accredited/certified local laboratory for all subjects 
see Section 9.9 or if results are available from standard of care and are within 
15 days prior to the visit these values may be used instead of requiring an 
additional blood draw; 
o In subjects randomized to VKA, obtain the subject’s INR records from 
previous visit(s) through to the current visit (inclusive) 
• Physical examination (details under Section 6.2) 
• Record vital signs (blood pressure and heart rate after the subject has been resting 
at least 5 minutes in a sitting position; body temperature, and weight) 
• If not part of standard of care, a 12-lead ECG will be performed. The results of 
any ECG will be recorded in the eCRF 
• If echocardiography (TTE or TEE) has been performed at any time as medically 
indicated or as per local standard of care for TAVI, the results will be recorded as 
specified on eCRF. 
• Confirm consent to participate in Post Discontinuation/Follow-up Contact; 
Transition subject to appropriate medication (Section 5.2.1)Note: In subjects with early 
permanent discontinuation of the assigned therapy every attempt made to have the 
Follow-up Visit performed. 
6.5.1. 
Transition from Study Medication to Standard of Care VKA 
Before transitioning to open-label VKA, all non-transition kit study supplies must be 
retrieved from the subject to avoid drug administration errors. For information on 
transitioning of medication, see Section 5.2.1. 
The subjects on Edoxaban will use the Sponsor provided transition kit to transition from 
Edoxaban to a VKA. The choice of VKA will be made by the Investigator in 
consultation with the subject’s personal physician and per local guidelines. More 
information on this transition from Edoxaban to open-label VKA is available in 


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Section 5.2.1. Subjects on VKA may be transitioned to another locally approved VKA 
following local guidelines. 
 
6.6. 
Post-treatment Follow-up Visit 
The Follow-up Visit will be 30 days (± 7 days) after the last study treatment. 
The Follow-up Visit activities are listed below: 
• Perform physical examination; 
• Record vital signs (blood pressure and heart rate after the subject has been resting 
at least 5 minutes in a sitting position; body temperature, and weight); 
• Check INR and recommend any dose adjustments to subject’s personal physician; 
• Blood draw for analysis by an accredited/certified local laboratory, the clinical 
laboratory tests (see Section 9.9) or if results are available from standard of care 
and are within 15 days prior to the visit these values may be used instead of 
requiring an additional blood draw; 
• Assessment and recording of (S)AEs and suspected clinical events since last visit; 
Assessment of any hospitalization for cardiovascular causes (such as shock, 
arrhythmia, cardiac rupture, stroke, aneurysms, stent occlusions, etc.) or bleeding; 
• Record any changes in concomitant medications; 
• Confirm consent to participate in Post Discontinuation/Follow-up Contact; 
• For childbearing potential female subjects, a urine pregnancy test (e.g., dipstick 
test) will be performed. 
 
6.7. 
Post Discontinuation/Follow-up Contact 
• Subjects (unless they refuse to participate) will be called approximately every 
6 months (± 1 month) until the Sponsor determines the end of the study to 
assess the subject’s vital status, occurrence of potential endpoint events, or 
any SAEs. This information may be obtained from relatives, public records, 
or the treating physician. Should the subject choose to not receive phone 
calls, the site may attempt to retrieve this information from viewing the 
subject’s medical records or public records. 


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7. 
OUTCOME ASSESSMENTS 
7.1. 
Bleeding 
Bleeding for the purpose of endpoints will be classified according to the ISTH definitions 
(see Section 17.1.1 and Section 9.1.1). Bleeding events will also be classified according 
to BARC (Section 17.1.3), TIMI (Section 17.1.2), and GUSTO (Section 17.1.4) 
classifications. 
 
7.2. 
Primary Efficacy Parameters 
NACE, i.e., the composite of all-cause death, MI, ischemic stroke, SEE, valve 
thrombosis, and major bleeding (ISTH definition) 
 
7.3. 
Primary Safety Parameters 
Major bleeding (ISTH definition) 
 
7.4. 
Secondary Endpoints (All Exploratory) 
7.4.1. 
Secondary Efficacy Endpoints 
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, 
valve thrombosis, and major bleeding (TIMI definition); 
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, 
valve thrombosis, and major bleeding (BARC 3 or 5 definition); 
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, 
valve thrombosis, and major and moderate bleeding (GUSTO definition); 
• Major Adverse Cardiac Events (MACE), defined as the composite of all-cause 
death (excluding adjudicated non-cardiac death), MI, or repeat coronary 
revascularization of the target lesion; 
• Major Adverse Cardiac and Cerebrovascular Events (MACCE), defined as the 
composite of all-cause death (excluding adjudicated non-cardiac death), MI, 
stroke (ischemic, hemorrhagic, or undetermined), or repeat coronary 
revascularization of the target lesion; 
• Cardiovascular mortality 
• Stroke (ischemic, hemorrhagic, or undetermined); 
• Stroke (ischemic); 
• Stroke (hemorrhagic); 
• Stroke (undetermined) 
• Fatal stroke (ischemic, hemorrhagic, or undetermined); 
• Non-fatal stroke (ischemic, hemorrhagic, or undetermined); 
• SEE; 
• Myocardial Infarction; 
• Valve thrombosis; 


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7.4.2. 
Secondary Safety Endpoints 
• Bleeding defined as TIMI major or minor, BARC 3 or 5, and GUSTO 
moderate or severe; 
• Bleeding defined as ISTH major and CRNM; TIMI major/minor bleeds or 
requiring medical attention; BARC 2, 3 or 5; and GUSTO moderate or severe; 
• Bleeding defined as ISTH CRNM, TIMI minor or requiring medical attention, 
BARC 2, and GUSTO moderate; 
• All bleeding that are not ISTH major, CRNM, TIMI minimal, BARC 1 non- 
actionable, and GUSTO mild; 
• Any bleeding; 
• Intracranial hemorrhage; 
• Life-threatening bleeding; 
• Fatal bleeding (fulfilling the ISTH major bleeding definition); 
• Non-fatal major bleeding (ISTH definition); 
• All-cause mortality; 
• Cardiovascular mortality; 
• 
Safety parameters such as (serious) adverse events, laboratory parameters, 
ECG and vital signs 
 
7.4.3. 
Other Endpoints 
• Number of hospital admissions, defined as ≥ 24 h stay in the hospital, due to 
cardiovascular causes (post TAVI and non-TAVI procedure related), including but 
not limited to overall, for bleeding, SEE, venous thrombosis, shock, 
arrhythmia, cardiac rupture, stroke, aneurysms, stent occlusions, etc. 
o Note: Hospital admissions due to cardiovascular causes include, but are 
not limited to the Emergency Department, ICU, and cardiovascular 
ward. 
• Treatment satisfaction as assessed by the PACT-Q 
• Health related quality of life as assessed by the EQ-5D-5L Questionnaire 
• Optional: Sub-studies not interfering with the main study may be added 
including such as the assessment of biomarkers of hemostasis/coagulation and 
of cardiovascular risk such as but not limited to WBCT, TEG, and MEA, 
Hs-TnT, GDF‐15, and cystatin‐C. 
All clinical endpoints will be analyzed as time to first occurrence of any of its 
components. 
All relevant NACE components will be adjudicated by the CEC in a blinded manner. For 
all clinical endpoints blindly adjudicated by the CEC, the CEC’s interpretation prevails 
and will be used in the statistical analysis. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
Not applicable 
 
8.1. 
Immunogenicity 
Not applicable 
 
8.2. 
Pharmacogenomic Analyses 
Not applicable 


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9. 
SAFETY EVALUATION AND REPORTING 
Safety assessments that are components of the study endpoint assessments (e.g., bleeding 
endpoints) are detailed in Section 7.3 and Section 7.4.2 and must be collected in the 
AE/Outcome eCRF page(s). 
 
9.1. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 9.3.1 for definitions) occurring after the subject signs the 
Informed Consent Form and up to 30 days after the last dose of study medication (i.e., the 
follow-up period), whether observed by the Investigator or reported by the subject, will 
be recorded on the Adverse Event eCRF page. 
Subjects who permanently discontinue study medication but continue in the study will be 
followed up every 6 months for collection of vital status (not vital signs) including 
collection of SAE and/or endpoint event reporting until the end of study (see Section 6.7). 
Medical conditions (including laboratory values/vital signs that are out of range) that 
were diagnosed or known to exist prior to Informed Consent will be recorded as part of 
medical history. 
All serious adverse events (SAEs), are to be reported according to the procedures in 
Section 9.6. 
• All laboratory results, vital signs, ECG, and any other imaging results or 
findings should be appraised by the Investigator to determine their clinical 
significance. Isolated abnormal laboratory results, vital sign findings, or ECG 
findings (i.e., not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study drug discontinuation, dose reduction, 
require corrective treatment, or constitute an AE in the Investigator’s clinical 
judgment. 
• At each visit, the Investigator or qualified designee will determine whether 
any AEs have occurred by evaluating the subject. Adverse events may be 
directly observed, reported spontaneously by the subject, or by questioning the 
subject at each study visit. Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms. The 
Investigator must assess all AEs to determine seriousness, severity, and 
causality, in accordance with the definitions in Section 9.3. The Investigator’s 
assessment must be clearly documented in the site’s source documentation 
with the Investigator’s signature. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available. If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report them as individual 
entries of AE or SAE. 
For events that are defined as serious due to hospitalization, the reason for hospitalization 
must be reported as the serious adverse event (diagnosis or symptom requiring 


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hospitalization). A procedure is not an AE or SAE, but the reason for the procedure may 
be an AE or SAE. 
Pre-planned (prior to signing the ICF) procedure or treatment requiring hospitalization 
for pre-existing conditions which do not worsen in severity should not be reported as 
SAEs (see Section 9.3.4 for definitions). 
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE. 
Investigator should follow subjects with adverse events until the event has resolved or the 
condition has stabilized. In case of unresolved adverse events including significant 
abnormal laboratory values at the end of study assessment, these events will be followed 
up until resolution or until they become clinically not relevant. 
In the following differentiation between medical history and AEs, the term “condition” 
may include abnormal physical examination findings, symptoms, diseases, laboratory, 
ECG, or any other imaging findings: 
Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history 
(e.g., seasonal allergy without acute complaints). 
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis). 
Conditions that started or deteriorated after the first dose of drug will be documented as 
adverse events; these include intercurrent illnesses. 
 
9.1.1. 
Bleeding 
All bleeding events will be reported in the eCRF as either an AE or SAE depending upon 
the seriousness criteria (see Section 9.6 for additional details). 
Bleeding requiring medical attention will be adjudicated by the CEC based on ISTH (see 
Section 17.1.1). Bleeding events that do not require medical attention will be classified 
as minor bleeding without CEC adjudication. 
The CEC will require all available details about the bleeding event and related 
information to allow successful objective adjudication of the event. Details may include, 
but are not limited to, information such as the following: 
• Location of the bleeding 
• Timing of the bleeding event: association with adherence of study drug, 
medications, and procedures 


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• Treatment for bleeding event, including notes or summary of the 
recommendations from a healthcare professional from whom medical treatment 
was obtained 
• Magnitude of the bleeding (including size if skin or subcutaneous hematoma) 
• Hemoglobin levels at randomization and at the time of the bleeding event, lowest 
value, pre- and post-transfusion values, and after resolution of the bleeding event 
• Diagnostic tests for the evaluation of the bleeding such as endoscopy 
(gastrointestinal bleed), ear, nose, and throat consult (ear, nose, throat bleed), 
urology consult (hematuria or urogenital bleeding), surgical consult (skin and 
soft tissue, including intraabdominal bleeding), gynecological consult (uterine or 
vaginal bleeding), neurological consult (intracranial bleed), or ophthalmology 
consult (intraocular bleed) 
• Diagnostic scans (CT scans or MRIs), ultrasounds, or x-rays performed to 
evaluate the bleeding (intracranial bleed) 
• Any other information that can be of help to the CEC to allow successful 
objective adjudication of the bleeding event. 
 
9.2. 
Events of Special Interest 
9.2.1. 
Combined Elevations of Aminotransferases and Bilirubin 
There is no clinically concerning signal of drug-induced liver injury associated with 
Edoxaban based on the extensive global Phase 3 experience involving over 34 048 
Edoxaban subject-years exposure (with median drug exposure of ≈2.5 years among 
18 010 Edoxaban treated subjects). 
However, there will be ongoing monitoring of hepatic events with particular attention to 
combined elevations of aminotransferases and bilirubin (ALT or AST > 3 x ULN with 
simultaneous total bilirubin levels > 2 x ULN), without evidence of cholestasis (ALP > 2 
x ULN is considered evidence of possible cholestasis) where no etiology for 
hepatocellular damage has been identified and a causal relationship to study drug cannot 
be ruled out. 
Combined elevations of aminotransferases and bilirubin meeting the laboratory criteria of 
a potential Hy’s Law case [ALT or AST ≥ 3 x ULN with simultaneous total bilirubin 
levels ≥ 2 x ULN] irrespective of whether they are serious or non-serious and whether 
causally related or not to study drug should always be reported to the Sponsor within 
24 hours of the Investigator becoming aware of the event following the procedures 
outlined in Section 9.5. 
In cases of liver laboratory abnormalities, or where there is evidence of liver dysfunction, 
it is important to ensure that the nature and the extent of liver injury is identified, and 
study subjects are monitored until the liver laboratory assessments return to normal. 


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If the subject discontinues study drug due to liver enzyme abnormalities, the subject will 
have additional clinical and laboratory evaluations which depending upon the clinical 
situation MAY include: 
• Abdominal ultrasound; 
• Hepatitis A, B, C, and E screening (anti-HAV IgM, HBsAg, anti-HCV plus viral 
titer, and evaluation for Hep E); 
• Antinuclear antibody (ANA) and anti-SmAb; 
• Cytomegalovirus (CMV); 
• Epstein Barr virus (EBV); 
• Additional evaluations as deemed appropriate by the Investigator to exclude other 
causes of liver enzyme and bilirubin elevations. 
Subject’s follow-up will be required until the values (transaminases, total bilirubin, and 
direct bilirubin) return to baseline. All clinically significant hepatic enzyme 
abnormalities and/or hepatic events must be documented in the eCRF. An adjudication 
dossier should be submitted for events that led to study drug discontinuation or were 
reported SAEs, where no alternative etiology has been found after work-up and where 
causal relationship to study drug cannot be ruled out. 
The subject may re-start study medication if considered appropriate by the Investigator. 
 
9.2.2. 
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. 
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 form) and 
reported to the CRO medical monitor who will contact the Sponsor. 
If the pregnancy is to be terminated, the anticipated date of termination should be 
provided. If the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify the Sponsor. If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (i.e., post-partum complications, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly, including that in 
an aborted fetus), the Investigator should follow the procedures for reporting 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. 
9.3. 
Adverse Event 
9.3.1. 
Definition of Adverse Event 
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 


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therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory findings which should be 
considered adverse events. 
 
9.3.2. 
Unexpected Adverse Event 
An unexpected AE is an AE, the nature or severity of which is not consistent with the 
reference safety information of any of the study medications or co-administered 
medications. 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. Determination of expectedness 
is the responsibility of Daiichi Sankyo and not the Investigator. 
 
9.3.3. 
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. 
 
9.3.4. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe (International 
Council on Harmonisation [ICH] E2A Guideline. Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasia or development of drug dependency or drug abuse. 


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Notes: 
• Procedures are not AEs or SAEs, but the reason for the procedure may be an AE 
or SAE. 
• Pre-planned (prior to signing the Informed Consent Form) procedures or 
treatments requiring hospitalizations for pre-existing conditions that do not 
worsen in severity are not SAEs. 
 
9.3.5. 
Severity Assessment 
The following definitions should be used to assess intensity of adverse events: 
• Mild: Awareness of sign or symptom, but easily tolerated, i.e., does not interfere 
with subject’s usual function. 
• Moderate: Discomfort enough to cause interference with usual activity. 
• Severe: Incapacitating with inability to work or do usual activity, i.e., interferes 
significantly with subject’s usual function. 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event 
whereas the event itself; however, may be of relatively minor medical significance (such 
as severe headache). This is not the same as "seriousness," which is based on 
subject/event outcome at the time of the event. 
 
9.3.6. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event and the study 
drug on the basis of his/her clinical judgment and the following definitions. The 
causality assessment must be made based on the available information and can be 
updated as new information becomes available. 
• 1 = Related: 
− The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s clinical 
state or other factors (e.g., disease under study, concurrent diseases, and 
concomitant medications). 
or 
− The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its chemical 
group, or is predicted by known pharmacology. 
• 2 = Not Related: 
− The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the subject’s clinical state 
or other factors (e.g., disease under study, concurrent diseases, and 
concomitant medications). 
 
9.3.7. 
Action Taken Regarding Study Drug(s) 
• 1 = Dose Not Changed: No change in study drug dosage was made. 


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• 2 = Drug Withdrawn: The study drug was permanently stopped. 
• 3 = Dose Reduced: The dosage of study drug was reduced. 
• 4 = Drug Interrupted: The study drug was stopped for a period of time. 
• 5 = Dose Increased: The dosage of study drug was increased. 
• Not Applicable: (e.g., Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment) 
 
9.3.8. 
Other Action Taken for Event 
1 = None: No treatment was required. 
2 = Concomitant medication required: Prescription and/or over-the-counter 
medication were required 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. 
 
9.3.9. 
Adverse Event Outcome 
1 = Recovered/Resolved: The subject fully recovered from the adverse event with 
no residual effect observed. 
2 = Recovered/Resolved with Sequelae: The residual effects of the adverse event 
are still present and observable. Include sequelae/residual effects. 
3 = Not Recovered/Not Resolved: The adverse event itself is still present and 
observable. 
4 = Fatal 
5 = Unknown 
The 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. 
 
9.4. 
Timing of Adverse Event Reporting 
All AEs must be recorded and reported from the stated starting point of the clinical trial 
(immediately after signing ICF) including AEs taking place during the administration of 
other drugs. Even if the subject has not yet received the investigational treatment, 
untoward medical occurrences have to be treated as AEs. 
The period of AE reporting is defined as follows: 


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AEs that occur within 30 days after the last dose of the assigned study treatment, 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 study treatments, this study will report all 
(S)AEs occurring after the subject signs the IC and as long as the subject remains in the 
study or until the study is terminated by the Sponsor (i.e., the end of the study), whether 
observed by the Investigator or reported by the subject. All AEs will be recorded on the 
AE/Outcome eCRF page(s) and include: 
• Any components of the study endpoint assessments (see Section 7); 
• AEs that meet seriousness criteria (see Section 9.3.4); 
• AEs that result in interruption or discontinuation of the assigned study treatment; 
• 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. 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 part of medical history. 
All SAEs are to be reported as long as the subject remains in the study or until the study 
is terminated by the Sponsor (i.e., the end of the study) and according to the procedures 
in Section 9.6. Always report the diagnosis as the AE or SAE term. When a diagnosis is 
unavailable, report the primary sign or symptom as the AE or SAE term with additional 
details included in the narrative until the diagnosis becomes available. If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report them as individual 
entries of AE or SAE. For events that are serious due to hospitalization, the reason for 
hospitalization must be reported as the SAE (diagnosis or symptom requiring 
hospitalization). 
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 9.3.5 and Section 9.3.6. The Investigator’s assessment must be clearly 
documented in the site’s source documentation with the Investigator’s signature. 
9.6. 
Serious Adverse Event Reporting–Procedure for Investigators 
• SAEs (see Section 9.3.4 for definition) 
• Serious events that are also efficacy endpoints (stroke, transient ischemic attack, 
SEE, and myocardial infarction) and/or safety endpoints (bleeding) will be 
exempted from SAE processing and expedited reporting but will be captured in 


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the eCRF. These events are exempted as they are clinically anticipated events in 
the target treatment population and will be periodically reviewed by the DSMB in 
an unblinded manner to ensure prompt identification of any clinically concerning 
safety issues. 
• All SAEs resulting in death regardless of whether they are waived endpoints 
for processing and expedited reporting will be processed by the CRO for 
entry into the Sponsor's global safety database. 
In case of an occurrence of an SAE, the Investigator applies the following rules: 
• Ensure appropriate medical treatment and decide whether to discontinue or 
interrupt any of the study medications or co-administered 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 possible. 
• 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. 
 
9.7. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators, Institutional Review Boards 
(IRBs)/Ethics Committees (EtCs), and regulatory authorities of any suspected unexpected 
serious adverse reactions (SUSARs) occurring in other study centers or other studies of 
the investigational drug, as appropriate per local reporting requirements. Daiichi Sankyo 
and/or CRO will comply with any additional local safety reporting requirements. 
Detailed SAE processing, distribution and reporting will be laid out in sponsors SAE 
Flow Plan. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
study drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to 
inform the IRB/EtC per Sponsor’s instruction. 
In the European Economic Area (EEA) states, it is the Sponsor’s responsibility to report 
SUSARs to all ECs. 


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9.8. 
Exposure In Utero During Clinical Studies 
While this should not be applicable, should it occur, see Section 9.2.2 for further details. 
 
9.9. 
Clinical Laboratory Evaluations 
Information will be entered in the case report form on whether or not measured, date of 
measurement, and measurement results and the local laboratory ranges for the following 
items. 
The results will be reviewed and compared to the local accredited/certified laboratory’s 
normal ranges. The visits at which these samples will be collected are shown in the 
schedule of assessments (Table 17.1). 
The following safety laboratory evaluations are performed: 
• Serum Chemistry Panel 
o 
Creatinine 
o Sodium (Na+) 
o Potassium (K+) 
o Chlorine (Cl-) 
o Blood urea nitrogen (BUN) 
o Glucose 
• Complete Blood Count (CBC) Panel: Including Hemoglobin, Hematocrit, 
WBC, Platelet Count 
• INR (only for subjects on VKA) 
• Urine pregnancy test (e.g., dipstick test), for childbearing potential female 
subjects at Randomization, 3 months, 12 months, 24 months, and End of 
Treatment Visits. 
• Serum pregnancy test at time of Screening for women of child bearing potential 
who are female subjects who are of child bearing potential. 
A liver function panel (total bilirubin [conjugated/unconjugated performed when total 
serum bilirubin ≥ 2 mg/dL], ALT, AST, ALP) will be performed at Screening (only if a 
recent, within the 15 days before randomization, is not available), and at the 6 Month and 
12 Month Visits. 
All other assessments are collected from local laboratory results for tests done as part of 
routine care. Local laboratory assessments are used for parameters required to verify 
eligibility and for parameters that require monitoring according to local routine. 
 
9.10. 
Vital Signs 
Blood pressure and heart rate will be measured at all specified visits (Table 17.1) after 
the subject has been resting at least 5 minutes in a sitting position, along with height 
(only at randomization), body temperature, and body weight. 


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9.11. 
Electrocardiograms 
The ECG will be recorded after the subject has rested in a recumbent position for 5 
minutes or more. The date performed, results, and any clinically significant findings for 
will be recorded in the case report form. 
If the ECG is not performed for any reason, the date and reason will be recorded in the 
case report form. 
 
9.12. 
Physical Examinations 
The Investigator or a licensed study team member will perform targeted physical 
examinations according to Table 17.1. As stated earlier, height is only needed once, 
usually at Screening. 
A physical examination will consist of assessment of each of the relevant (cardiac, 
pulmonary, gastrointestinal, dermatologic) major body systems. If a system is not 
assessed, the Investigator or designee will note the reason in the source documents. 
Assessment of other systems, including neurological, is not required per protocol, unless 
determined as necessary per investigator discretion for further evaluation of a suspected 
AE (eg., Stroke or TIA), or suspected outcome event. 


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10. 
OTHER ASSESSMENTS 
10.1. 
Healthcare Resource Utilization 
Data for each hospitalization post TAVI but non-TAVI procedure related that are due to 
cardiovascular causes (such as shock, arrhythmia, cardiac rupture, stroke, aneurysms, 
stent occlusions, etc.), including data on admission and discharge dates, hospital ward 
(e.g., emergency department, intensive care unit, cardiovascular ward), admission 
diagnosis and status post TAVI will be collected. 
• Bleeding 
• Ischemic stroke 
• SEE 
• Myocardial infarction 
• 
Valve thrombosis 
• Other cardiovascular causes 
10.2. 
Perception Anticoagulant Treatment Questionnaire (PACT-Q) 
The Perception of Anticoagulant Treatment Questionnaire (PACT-Q) was developed to 
assess subjects’ expectations of, and satisfaction with their anticoagulant treatment. The 
psychometric properties of the PACT-Q have been reported previously. The PACT-Q 
consists of two modules. The first module, PACT-Q1, contains 7 items, each 
individually scored from 1 to 5, with higher score indicating higher subjects’ expectation 
for their treatment. The second module, PACT-Q2, is constituted of two dimensions: 
Convenience (11 items) and Anticoagulation Treatment Satisfaction (7 items). Items in 
the Convenience dimension are reversed scored, summed and rescaled on a 0 to 100 scale 
such that the higher the score indicates a treatment to be more convenient and less 
burdensome as perceived by the subject. Items in the Anticoagulation Treatment 
Satisfaction dimension are summed and rescaled on a 0 to 100 scale. Higher score 
indicates higher satisfaction with anticoagulation treatment. 
The PACT-Q1 will be administered to study subjects at randomization. The PACT-Q2 
will be administered to study subjects at 3 months and either12 months or the EOT 
whichever comes first. A copy of the PACT-Q1 and PACT-Q2 will be provided to the 
sites. 
 
10.3. 
EuroQoL (EQ-5D-5L) Questionnaire 
The EQ-5D-5L is standardized measure of health status developed by the EuroQoL 
Group in order to provide a simple descriptive profile and a single health status index. 
The EQ-5D-5L consists of two measures: 1) the EQ-5D-5L descriptive system and 2) the 
EQ Visual Analogue Scale (EQ VAS). The EQ-5D-5L descriptive system asks the 
subject to provide rating on each of the five dimensions of health: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. The EQ VAS records the 
subject’s overall health on a 0 to 100 analogue scale anchored from “best imaginable 
health state” to “worst imaginable health state”. 


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The EQ-5D-5L is designed for self-completion by study subjects and takes only 1 to 
2 minutes to complete. The EQ-5D-5L will be administered for study subjects at 
randomization, 3 months and either12 months or the EOT whichever comes first. A copy 
of the EQ-5D-5L will be provided to the sites. 


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11. 
STATISTICAL METHODS 
11.1. 
Analysis Sets 
In the following subsections only the analysis sets for the statistical analyses of efficacy 
and safety parameters are defined. Other analysis sets (e.g., health economics outcome 
research [HEOR]) will be defined in the Statistical Analysis Plan (SAP) as needed. 
 
11.1.1. 
Intention-to-treat Analysis Set 
The Intention-to-treat Analysis Set (ITT) consists of all randomized subjects irrespective 
of whether they received a single dose of study Edoxaban or VKA or not. 
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 randomization. 
 
11.1.2. 
Modified Intention-to-treat Analysis Set 
The modified 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. 
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 randomized 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: 
o A major violation of the inclusion criteria 
o An unequivocal violation of the exclusion criteria 
The list of major violations will be finalized before database 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 the date and time of first intake of study Edoxaban or 
study VKA. 


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11.1.4. 
Safety Analysis Set 
The Safety Analysis Set (SAF) 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 
the incorrect drug(s) or dosage during the entire study, in which case the subject will be 
grouped according to the treatment actually received. 
Note: This SAF analysis set will be used for the safety parameters (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 ≥ 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 variables, 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 deviation and other dispersion statistics will have two more decimal 
places; and minimum and maximum values will be displayed to the same number of 
decimal 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 (i.e., 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. 


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Definition of terms: 
’Overall Study Period’: This period is defined as the time from the reference date up to 
an estimated Month 36/EOT (Visit 8). 
’Overall Study Period + 30 days’: This period is defined as the time from the reference 
data up to an estimated Month 36/EOT (Visit 8) + 30 days, i.e., to Month 37 (post- 
treatment FU visit). 
‘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 
and time of final dose of study Edoxaban or study VKA + 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 of 
study Edoxaban or study VKA. 
The main analyses of adjudicated primary and secondary exploratory endpoints 
(Section 7.2, Section 7.3, and Section 7.4, 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 drugs (Edoxaban, VKA, P2Y12 antagonist, and ASA) will be 
summarized using descriptive statistics by treatment regimen for the mITT, PP and SAF 
analysis sets. Interruptions and permanent discontinuations (see Section 5.8) will be 
summarized by treatment group for the same analysis sets. 
The time in therapeutic range (TTR) (INR: 2.0 to 3.0, numbers inclusive) [Japan: 1.6 to 
2.6 in subjects age ≥70 (numbers 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 Analyses 
For each of the primary and secondary efficacy and safety endpoints, appropriate 
summary statistics (e.g., event rate) including 95% confidence interval (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 randomization 
(IXRS) as covariates, dose adjustment [yes, no], to provide point estimates and 95% 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 
on an individual basis for subjects with incomplete follow-up. 
The parameter estimate β (= ln (Hazard ratio), its standard error, p-value, and 95% 
confidence limits are calculated according to the maximum partial likelihood method, 
with Breslow’s approximation for ties (SAS PHREG procedure). 
For time to first event analyses, cumulative event rates over time are summarized using 
the Kaplan-Meier method as appropriate. 
 
11.4.1. 
Analysis of the primary endpoint(s) 
The primary efficacy endpoint is NACE, i.e., the composite of all-cause death, MI, 
ischemic stroke, SEE, valve thrombosis, and major bleeding (ISTH definition). 
The primary safety endpoint is major bleeding (ISTH definition). 
There are 4 primary hypotheses that will be tested in hierarchical order: 
• Hypothesis (1): 
o The Edoxaban-based regimen is noninferior to the VKA-based regimen 
with regards to NACE. 
• Hypothesis (2): 
o The Edoxaban-based regimen is noninferior to the VKA-based regimen 
with regards to major bleeding (ISTH definition). 
• Hypothesis (3): 
o The Edoxaban-based regimen is superior to the VKA-based regimen with 
regards to major bleeding (ISTH definition). 
• Hypothesis (4): 
o The Edoxaban-based regimen is superior to the VKA-based regimen with 
regards to NACE. 


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The analysis set and analysis periods to be used for the main analysis related to these four 
hypotheses are presented below: 
Table 11.1: 
Statistical Analysis Hierarchy for Primary Parameters 
 
Hypothesis 
Endpoint 
Primary Analysis 
Set 
Primary Analysis 
Period 
(1) 
NACE 
ITT 
Overall study 
period 
(2) 
Major bleeding 
(ISTH def) 
ITT 
Overall study 
period 
(3) 
Major bleeding 
(ISTH def) 
ITT 
Overall study 
period 
(4) 
NACE 
ITT 
Overall study 
period 
To control the type-I error rate, these four hypotheses will be tested in a hierarchical 
manner: 
• Step (1): The Edoxaban-based regimen will be considered noninferior to the 
VKA-based regimen with regards to NACE, if the upper boundary of the two- 
sided 95% CI for hazard ratio (HR) falls below 1.38. If it is significant, then go to 
Step (2), otherwise stop here. 
• Step (2): The Edoxaban-based regimen will be considered noninferior to the 
VKA-based regimen with regards to major bleeding (ISTH def.), if the upper 
boundary of the two-sided 95% CI for HR falls below 1.38. If it is significant, 
then go to Step (3), otherwise stop here. 
• Step (3): The Edoxaban-based regimen will be considered superior to the VKA- 
based regimen with regards to major bleeding (ISTH def.), if the upper boundary 
of the two-sided 95% CI for HR falls below 1.00. If it is significant, then go to 
Step (4), otherwise stop here. 
• Step (4): The Edoxaban-based regimen will be considered superior to the VKA- 
based regimen with regards to NACE, if the upper boundary of the two-sided 95% 
CI for HR falls below 1.00. 
For each of the primary and secondary adjudicated endpoints, appropriate summary 
statistics (e.g., event rate) including 95% CI will be provided. 
For each of the adjudicated 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 
randomization (IXRS) [dose adjustment [yes, no]] 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 


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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. 
To evaluate the robustness of the primary analyses, the analyses 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’ and ‘overall study period + 30 
days’ will be presented and will be interpreted in a more descriptive way. Results for 
other combinations of analysis sets and analysis periods may be presented if considered 
necessary. 
For time to first event analyses based, cumulative event rates over time are summarized 
using the Kaplan-Meier method as appropriate. 
 
11.4.2. 
Analyses of the secondary exploratory endpoints 
The main analyses for all secondary efficacy and safety 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 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 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’ and ‘overall 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 Analyses 
 
11.4.3.1. Pharmacokinetic Analyses 
Not applicable. 
 
11.4.3.2. Pharmacodynamic Analyses 
Not applicable. 
 
11.4.3.3. Biomarker Analyses 
A potential sub-study is possible which will have a separate analysis plan. 
 
11.4.3.4. Pharmacogenomic Analyses 
Not applicable. 
 
11.4.4. 
Health Economics Outcome Research (HEOR) Analyses 
For healthcare resource utilization, proportion of subjects with hospitalization, number of 
hospitalizations, and length of hospital stay related to cardiovascular events of protocol 


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interest during the study will be described using summary statistics and compared 
between treatments. 
For the PACT-Q, the absolute PACT-Q1 item scores and change from baseline values at 
the 12 months (or end of treatment if earlier) will be described using summary statistics 
and compared between treatments. In addition, the PACT-Q2 Convenience and 
Treatment Satisfaction scores will be summarized at each scheduled time point 
(Table 17.1) and compared between treatment groups. 
For the EQ-5D-5L, the absolute and change from baseline values for the five domain 
scores, the EQ-5D-5L index value, and the EQ VAS score will be described using 
summary statistics by scheduled time point and compared between treatments. 
Additional details will be provided in the SAP. 
 
11.5. 
Safety Analyses 
All safety analyses described in this section will be based on the Safety analysis set. 
 
11.5.1. 
Adverse Event Analyses 
Adverse events meeting the criteria defined in Section 9.3 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. 
TEAEs will be summarized by treatment group. The 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 once for 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% 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 9.3.4 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 will be summarized 
descriptively by treatment regimen and visit (including changes from baseline). The 
baseline value is defined as the last non-missing value before first administration of study 
medication. In addition, descriptive statistics will also be presented for the maximum and 
minimum post baseline values (including changes from baseline). Shift tables (in 


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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. 
More 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 by 
treatment regimen. The baseline value is defined as the last non-missing value before 
first administration of study medication. In addition, descriptive statistics will also be 
presented for the maximum and minimum post baseline values (including changes from 
baseline). 
More details will be outlined in the SAP. 
 
11.5.4. 
Physical Examination Analyses 
A physical examination (Section 9.12) will be performed at the Randomization Visit, End 
of Treatment Visit, and the Post-treatment FU Visit. The physical examination findings 
will be summarized by treatment regimen based on the SAF analysis set. 
More details will be outlined in the SAP. 
 
11.5.5. 
Electrocardiogram Analyses 
The ECG evaluations at baseline and at all post baseline visits including the FU visit will 
be summarized by treatment regimen based on the SAF analysis set. 
More details will be outlined in the SAP. 
 
11.6. 
Other Analyses 
If applicable, details on other analyses will be provided 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 on an ongoing manner 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 specified in the DSMB Charter. 


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11.9. 
Sample Size Determination 
In order to determine the sample size, the following assumptions were made: 
• Event rate: Based on published literature and results from the ENGAGE AF- 
TIMI 48 study, it is assumed that the event rate of the primary efficacy endpoint 
of NACE in AF-subjects with TAVI treated with VKA would be 14%/year. 
• Noninferiority margin: No data were available for placebo-controlled studies in 
this subject population. The Executive Committee reviewed all available data 
including practice changes observed in other areas of cardiology on the basis of 
clinical trials and the level of statistical certainty they had achieved. Then it made 
the judgment that a noninferiority margin for hazard ratio 1.38 would be accepted 
by the medical community for a practice change given the fact that other trials 
have already supported the use of Edoxaban in subjects warranting 
anticoagulation and its related regulatory approval for human use in the 
participating countries. 
• Significance level for statistical testing: 0.05. 
• Observed hazard ratio: 0.95. 
With the above assumptions, to demonstrate noninferiority with 80% of power, the study 
needs to collect at least 320 NACE across the combined study arms. With an anticipated 
median follow-up time of two years and an annual event rate of 14%, a total of 
approximately 1400 subjects need to be randomized. 
The sample size is event driven. The sample size or the duration of follow-up may 
require adjustment based on the actual versus anticipated primary endpoint event and 
drop-out rates. 
 
11.10. 
Statistical Process 
The statistical analysis will be performed by the assigned CRO under the guidance of the 
Daiichi Sankyo study biostatistician. 
A Statistical Analysis Plan will be written providing all the details on the statistical 
methods and definitions for the analysis of the efficacy and safety data, as well as 
describing the approaches to be taken for summarizing other clinical study information 
such as, but not limited to, subject disposition, demographic and baseline characteristics, 
study drug exposure, and prior and concomitant medications. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP 
will be finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS 
Institute, Cary, NC 27513). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, 
IRB/EtC 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. 
Furthermore, the Investigator/investigational site will supply the CEC with whatever 
information that is requested such that the CEC will be able to perform their adjudication 
duties. 
 
12.1. 
Monitoring and Inspections 
The monitor and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (e.g., eCRFs, source data, and other pertinent 
documents). 
The monitor is responsible for visiting site(s) at regular intervals (as detailed in the 
monitoring plan) depending upon the site enrollment and monitoring needs of the site, 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to ICH Good Clinical Practice (GCP) and local 
regulations on the conduct of clinical research. The monitor is responsible for inspecting 
the eCRFs 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 eCRFs. Source document verification procedure and process is 
addressed in the study monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are addressed and documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from the Sponsor. Inspection of site facilities (e.g., 
pharmacy, drug storage areas, laboratories, etc.) and review of study related records will 
occur in order to evaluate the study conduct and compliance with the protocol, ICH GCP, 
and applicable regulatory requirements. 
12.2. 
Data Collection 
This study employs electronic data capture. The eCRF should be kept current to enable 
the monitor to review the subject’s status throughout the course of the study. The eCRF 
will be completed, reviewed, and electronically signed by the Investigator. Guidelines 
will be provided to facilitate data entry in the electronic data capture modules. 
All written information, study notes, and other material to be used by subjects and 
investigative staff must use vocabulary and language that are clearly understood as source 
documentation. 


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12.3. 
Data Management 
All data management related tasks, responsibilities, and processes are noted in the data 
management plan for the study. 
Each subject will be identified in the database by a unique subject identifier as defined by 
the Sponsor. 
To ensure the quality of clinical data across all subjects and study centers, a Clinical Data 
Management review will be performed on subject data according to specifications given 
by the Sponsor or designee(s). Data will be vetted both electronically and manually for 
CRFs and the data will be electronically vetted by programmed data rules within the 
application. Queries generated by rules and raised by reviewers will be generated within 
the electronic data capture application. During this review, subject data will be checked 
for consistency, completeness and any apparent discrepancies. In addition, the data will 
be reviewed for adherence to the protocol and GCP. To resolve any questions arising 
from the Clinical Data Management review process, eCRF queries will be raised and 
resolved within the electronic data capture application. 
Data received from external sources such as laboratories and IXRS will be reconciled to 
the clinical database. 
Serious Adverse Events in the clinical database will be reconciled with the safety 
database. 
All medical history entries (except terms pre-specified on the eCRF) and AEs will be 
coded using MedDRA. All prior and concomitant medications will be coded using 
World Health Organization (WHO) Drug Dictionary. 
 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature Log of appropriately qualified persons to 
whom he/she has delegated study duties. All persons authorized to make entries and/or 
corrections on CRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited information of the subjects, date and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in 
the study indicating their assigned study number. 
Investigators will maintain a confidential Subject Identification Code Log. This 
confidential list of names of all subjects allocated to study numbers on enrolling in the 
study allows the Investigator to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained. These include but are not limited to hospital records, clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, x-rays, and 
correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) 


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documentation, suitable for inspection at any time by representatives from the Sponsor 
and/or applicable regulatory authorities. Essential documents include: 
• Subject files containing completed eCRFs, informed consent forms, and 
supporting copies of source documentation (if kept). 
• Study files containing the protocol with all amendments, Investigator’s 
Brochure, copies of relevant essential documents required prior to 
commencing a clinical study, and all correspondence to and from the IRB/EtC 
and the Sponsor. 
• Records related to the study drug(s) including acknowledgment of receipt at 
study center, accountability records and final reconciliation and applicable 
correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
All essential documentation will be retained by the institution until told otherwise by the 
Sponsors. 
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. 
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 another location, he/she must notify Sponsor in writing of 
the new responsible person and/or the new location. 
All Investigators and site personnel must ensure subject confidentiality as outlined 
in Section 15.2. 
12.5. 
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/EtC correspondence and approvals, approved and signed ICFs, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other Sponsor 
correspondence pertaining to the study must be kept in appropriate study files at the site. 
Source documents include all recordings and observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical study. These records will be retained in a secure file for the period required 
by the institution or site policy. Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to further store such 
records. 


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


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14. 
PUBLICATION POLICY 
 
CCI


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


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written ICF should be prepared in the local language(s) of the potential subject 
population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. The consent form and any 
revision(s) should be approved by the EtC or IRB prior to being provided to potential 
subjects. 
The subject’s written informed consent should be documented in the subject’s medical 
records. The ICF and the subject Assent Form should be signed and personally dated by 
the subject and by the person who conducted the informed consent discussion (not 
necessarily the Investigator). The original signed ICF should be retained in accordance 
with institutional policy, and a copy of the signed consent form should be provided to the 
subject. The date and time (if applicable) that informed consent was given should be 
recorded on the CRF. 
Suggested model text for the ICF for the study and any applicable subparts (PK, etc.) are 
provided in the Sponsor’s ICF template for the Investigator to prepare the documents to 
be used at his or her study center. Updates to applicable forms will be communicated via 
letter from the Sponsor. 
For studies in the US, an additional consent is required for the Health Insurance 
Portability and Accountability Act (HIPAA). 
 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator Brochure, any 
subject written instructions to be given to the subject, available safety information, 
subject recruitment procedures (e.g., advertisements), information about payments and 
compensation available to the subjects, and documentation evidencing the Investigator’s 
qualifications should be submitted to the EtC/IRB for ethical review and approval 
according to local regulations, prior to the study start. The written approval should 
identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator must submit and, where necessary, obtain approval from the EtC or IRB 
for all subsequent protocol amendments and changes to the ICF. The Investigator should 
notify the EtC/IRB of deviations from the protocol or SAEs occurring at the study center 
and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or 
representative to whom this responsibility has been delegated will ensure all legal aspects 
are covered, and approval from the appropriate regulatory bodies obtained, prior to study 
initiation, and that implementation of changes to the initial protocol and other relevant 
study documents happen only after approval by the relevant regulatory bodies. 


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In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Regulatory Authorities in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational drug, the Sponsor should be informed immediately. 
In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator 
becomes aware of. 
 
15.5. 
Protocol Deviations 
The Investigator shall conduct the study in compliance with the protocol agreed to by 
Sponsor and, if required, by the regulatory authority/ies, and which was given 
approval/favorable opinion by the IRBs/ECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject. 
Sponsor must be notified of all intended or unintended deviations to the protocol (e.g., 
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at 
least 1 administration of study drug, data should be collected for safety purposes. 
• If applicable, the Investigator should notify the IRB/EtC of deviations from 
the protocol in accordance with local procedures. 
 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects 
or the conduct of the study, the Sponsor will inform all Investigators involved in the 
clinical study, ECs/IRBs, and regulatory authorities of such information, and when 
needed, will amend the protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information 
becomes available that may be relevant to the subject’s consent or may influence the 
subject’s willingness to continue participation in the study. The communication should 
be documented on medical records, for example, and it should be confirmed whether the 
subject is willing to remain in the study. 
If the subject information is revised, it must be re-approved by the IRB/EtC. The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if subjects were already informed of the relevant 
information. The Investigator or other responsible personnel who provided explanations 
and the subject should sign and date the revised ICF. 


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15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the Investigator by the Sponsor or the CRO. Also, 
the Sponsor will ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study centers in all regions 
of the world. Such amendments will be incorporated into a revised protocol document. 
Changes made by such amendments will be documented in a Summary of Changes 
document. These protocol amendments will undergo the same review and approval 
process as the original protocol. 
A local protocol amendment will affect study conduct at a particular study center(s) 
and/or in a particular region/country. Sponsor approval of local amendments will be 
clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EtC 
and by regulatory authorities where appropriate, unless immediate implementation of the 
change is necessary for subject safety. 
 
15.8. 
Study Termination 
The independent DSMB may recommend termination of the study.  Termination may be 
made for any of the following reasons: 
• Concern about significantly higher bleeding risk relative to one of the study arms, 
• Any safety concerns based on benefit/risk evaluation. 
The DSMB will alert the Investigator or designee if there are any of the above concerns 
requiring protocol modifications or any other changes in the study. 
The details about the roles and responsibilities of the DSMB and guidelines and rules for 
monitoring the study safety data will be described further in the DSMB Charter. 
The Sponsor has the right to terminate the study at any time for commercial (budget) 
reasons, delayed recruitment, subject safety, or results from other research. The study 
termination may also be requested by (a) competent authority(ies). 
 
15.9. 
Data and Safety Monitoring Board 
An independent DSMB will be created to further protect the rights, safety, and well-being 
of subjects who will be participating in this study by monitoring their progress and 
results. The DSMB will comprise of qualified scientists, who are not Investigators in the 
study and not otherwise directly associated with the Sponsor. The DSMB will be 
described in detail in the DSMB Charter. The DSMB will monitor data during the study. 
All activities of the DSMB will be documented. This documentation will include data 
summaries and analyses provided to the committee as well as minutes of the meeting. 
The DSMB can recommend study or treatment regimen/group termination to the Study 
Oversight Committee based on pre-specified concerns described in the DSMB Charter. 


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The documentation will remain confidential 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. 
15.10. 
Clinical Events Committee 
An independent study specific CEC will review and adjudicate key endpoint events as 
outlined in the CEC Charter. 
The CEC will comprise qualified judges, who are not Investigators in the study and not 
otherwise directly associated with the Sponsor. The CEC judges will remain blinded to 
treatment throughout the adjudication process and the study. The CEC-adjudicated data 
will be used in the final efficacy and safety analyses. The CEC and the events it will 
adjudicate will be detailed in the CEC Charter. 
The Investigator/investigational site will supply the CEC with whatever information that 
is requested such that the CEC will be able to perform their adjudication duties. 
 
15.11. 
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 Committee will also review the progress of the study at regular intervals to 
ensure subject safety and study integrity. The Executive Committee will be composed of 
designated representatives from the CRO and Sponsor. 
15.12. 
Steering Committee 
A study Steering Committee will include the Executive Committee members and 
National Lead Investigators and 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. 
15.13. 
Operations Committee 
A, optional Operational 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 Committee on the progress 
of the study. 
15.14. 
Sub-studies 
Subjects in this study may participate in one or more sub-studies. Dedicated sites are 
invited for participation according to sites capabilities to meet specific sub-studies 
requirements and on the required number of observations. Currently, sub-studies are 
being considered involving: 


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• Parameters of hemostasis such as WBCT, TEG, and MEA. 
15.15. 
Address List 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and 
other vendors) and their contact information (address, telephone, fax, email) will be kept 
on file and updated in study reference materials. 


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16. 
REFERENCES 
1. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a 
population-based study. Lancet 2006; 368:1005-11. 
2. Otto CM, Prendergast B. Aortic-valve stenosis - from patients at risk to severe 
valve obstruction. NEJM 2014; 371:744-56. 
3. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve 
replacement in high-risk patients. NEJM 2011; 364:2187-98. 
4. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for 
aortic stenosis in patients who cannot undergo surgery. NEJM 2010; 363:1597- 
607. 
5. Yousef A, MacDonald Z, Simard T, et al. Transcatheter aortic valve implantation 
(TAVI) for native aortic valve regurgitation- a systematic review. Circ J 2018; 
82(3): 895-902. 
6. Silaschi M, Conradi L, Wendler O, Schlingloff F, et al. The JUPITER registry: 
One-year outcomes of transapical aortic valve implantation using a second 
generation transcatheter heart valve for aortic regurgitation. Catheter Cardiovasc 
Intery 2018; 91(7): 1345-51. 
7. Lindman BR, Pibarot P, Arnold SV, et al. Transcatheter versus surgical aortic 
valve replacement in patients with diabetes and severe aortic stenosis at high risk 
for surgery: an analysis of the PARTNER Trial (Placement of Aortic 
Transcatheter Valve). JACC 2014; 63:1090-9. 
8. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement 
using a self-expanding bioprosthesis in patients with severe aortic stenosis at 
extreme risk for surgery. JACC 2014; 63:1972-81. 
9. Rodés-Cabau J, Dauerman H, Cohen M, et al. Antithrombotic treatment in 
transcatheter aortic valve implantation: insights for cerebrovascular and bleeding 
events. JACC 2013; 25:2349-59. 
10. Rigshospitalet, Denmark. Comparison of transcatheter versus surgical aortic valve 
replacement in younger low surgical risk patients with severe aortic stenosis 
(NOTION-2). ClinicalTrials.gov Identifier: NCT02825134 
11. Généreux P, Cohen D, Mack M, et al. Incidence, Predictors, and prognostic 
impact of late bleeding complications after transcatheter aortic valve replacement. 
JACC 2014; 64: 2605-15. 
12. Rodés-Cabau J, Dauerman HL, Cohen MG, et al. Antithrombotic treatment in 
transcatheter aortic valve implantation: insights for cerebrovascular and bleeding 
events. JACC 2013; 62:2349-59. 
13. Ussia GP, Scarabelli M, Mulè M, et al. Dual antiplatelet therapy versus aspirin 
alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 
2011; 108:1772-6. 


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14. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter 
or surgical aortic-valve replacement. NEJM 2012; 366:1686-95. 
15. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve 
replacement for inoperable severe aortic stenosis. NEJM 2012; 366:1696-704. 
16. Holmes DR, Jr., Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS expert 
consensus document on transcatheter aortic valve replacement. JACC 2012; 
59:1200-54. 
17. Durand E, Blanchard D, Chassaing S, et al. Comparison of two antiplatelet 
therapy strategies in patients undergoing transcatheter aortic valve implantation. 
Am J Cardiol 2014; 113:355-60. 
18. Webb J, Rodés-Cabau J, Fremes S, et al. Transcatheter aortic valve implantation: 
a Canadian Cardiovascular Society position statement. Can J Cardiol 2012; 
28:520-8. 
19. Holmes DR, Jr., Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS expert 
consensus document on transcatheter aortic valve replacement: developed in 
collaboration with the American Heart Association, American Society of 
Echocardiography, European Association for Cardio-Thoracic Surgery, Heart 
Failure Society of America, Mended Hearts, Society of Cardiovascular 
Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society 
for Cardiovascular Magnetic Resonance. The Journal of Thoracic and 
Cardiovascular Surgery 2012; 144:e29-84. 
20. Dewilde WJ, Oirbans T, Verheugt FW, 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 2013; 
381:1107-15. 
21. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients 
with atrial fibrillation. NEJM 2013; 369:2093-104. 
22. Hokusai VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus 
warfarin for the treatment of symptomatic venous thromboembolism. NEJM 
2013; 369:1406-15. 
23. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve, 
replacement in intermediate-risk patients. NEJM 2016; 374:1609-20. 
24. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve 
replacement in high-risk patients. NEJM 2011; 364:2187-98. 
25. Leon MB, Smith CR, Mack M. Transcatheter aortic-valve implantation for aortic 
stenosis in patients who cannot undergo surgery. NEJM 2010; 363:1597-1607 
26. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine 
the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 
1993; 69:236-239. 


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27. Schulman S, Kearon C, and Subcommittee on Control of Anticoagulation of the 
S, Standardization Committee of the International Society on T and Haemostasis. 
Definition of major bleeding in clinical investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb Haemost. 2005;3:692-4. 
28. Mehran R, Rao SV, Bhatt DL, Gibson CM, et al. Standardized bleeding 
definitions for cardiovascular clinical trials: a consensus report from the Bleeding 
Academic Research Consortium. Circulation. 2011; 123:2736-47. 
29. Topol E, et al. An international randomized trial comparing four thrombolytic 
strategies for acute myocardial infarction. NEJM 1993; 329:673-82 
30. Mylotte D, Piazza N. Transcatheter aortic valve replacement failure: déjà-vu ou 
jamais vu? Circ Cardiovasc Interv 2015; 8: e002531 


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17. 
APPENDICES 


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Table 17.1: 
Table of Events of Treatment Period 
 
Visit Number 
1 
2* 
3* 
4* 
5* 
6* 
7* 
8* 
9* 
10 
Visit timing 
Screening 
Baseline/ran- 
domization 
(DAY 1) 
3 M 
±14d 
6 M 
±14d 
12M 
±14d 
18M 
±14d 
24M 
±14d 
30M 
±14d 
EOTl, m 
36 M ±14d 
Post 
treatment 
Follow-up 
1 M post 
EOT ± 7d 
Follow-up 
contact 
(every 6±1 
months 
after EOT)p 
Study informed consenta 
x 
Inclusion/Exclusion Criteria 
x 
Record EuroSCORE 1 and 
2, STS elements and CHAD 
and HAS-Bleed scores in 
eCRF 
x 
Check local lab resultsb 
x 
Demographic information 
x 
Medical/surgical history 
(including bleeding and for 
the past 30 days, 
medication history) 
x 
x 
Contact IXRS 
x 
xc 
Administer first study dose 
of OACd 
x 
Dispense assigned OACe 
x 
x 
x 
x 
x 
x 
x 
NA 
NA 
Collect unused medication 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
x 
Vital signsf 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Visit Number 
1 
2* 
3* 
4* 
5* 
6* 
7* 
8* 
9* 
10 
Visit timing 
Screening 
Baseline/ran- 
domization 
(DAY 1) 
3 M 
±14d 
6 M 
±14d 
12M 
±14d 
18M 
±14d 
24M 
±14d 
30M 
±14d 
EOTl, m 
36 M ±14d 
Post 
treatment 
Follow-up 
1 M post 
EOT ± 7d 
Follow-up 
contact 
(every 6±1 
months 
after EOT)p 
12-lead ECGg 
x 
x 
Blood drawh, INR 
recording 
xb 
x 
x 
x 
x 
x 
x 
x 
x 
PACT-Q1, Q2 and EQ-5D- 
5Li 
x 
x 
x 
x 
Review study regimen 
compliance & interruptionsj 
x 
x 
x 
x 
x 
x 
x 
NA 
Assessment and recording 
of (S)AEs and suspected 
clinical events including 
hospitalizationsk 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transition to open-label 
medicationl 
x 
Notify study team in case 
TTE or TEE or CT were 
performed as part of routine 
care and record parameters. 
x 
x 
x 
x 
x 
x 
x 
x 
NA 
Serum pregnancy testn 
x 
Urine pregnancy testo 
x 
x 
x 
x 
x 
Abbreviations: AE = adverse event; CBC= complete blood count; CrCL = creatinine clearance; CRO = clinical research organization; CT = computer 
tomography; d = day(s); ECG = electrocardiogram; echo = echocardiogram; eCRF = electronic case report form; EQ-5D-5L = EuroQuality of Life 
(EQ-5D-5L) Questionnaire; EOT = end of treatment; INR = international normalized ratio; IXRS = interactive web/voice response system; 
M = month(s); NA = not applicable; PACT-Q = Perception of Anticoagulant Treatment Questionnaire; OAC = oral anticoagulant; OAP = oral 
antiplatelet; SAE = serious AE; STS = Society of Thoracic Surgeons; TEE = transesophageal echo; TTE = transthoracic echo; ULN = upper limit of 
normal; VKA = Vitamin K antagonist. 


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* 
Visits may be on-site or at the subject’s current place of living, but must be conducted by the investigator or appropriately trained designee (see 
Section 6.4). 
a Subjects 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. 
b Check the most recent results from local laboratory tests done within the 15 days before randomization against the exclusion criteria. Creatinine and 
CBC must be available from blood draws after TAVI with the subject being clinically stable. CrCL should be calculated by the Cockcroft-Gault 
formula as described in Section 17.7 and the results should be available at each study visit in time to determine correct dosing for Edoxaban subjects. 
c Contact IXRS for randomization and pre-declaration of oral antiplatelet therapy by drug, dose, and projected last dose if applicable. Also contact 
IXRS for change in Edoxaban dosing, and prior to any distribution of Edoxaban; the end of Edoxaban treatment also needs to be recorded in IXRS. 
d First dose should be should be administered within the 5 days after TAVI (in case of pacemaker deployment within the 7days after TAVI) but within 
24 hours of randomization; however, NO EARLIER than the morning after successful TAVI. For suggested starting dosing see Section 5.2.1.1.1 and 
Section 5.2.1.2.1. Predefine and institute OAP (see Section 3.1). 
e Daiichi Sankyo supplies study subjects with Edoxaban. VKA and OAP will be provided or prescribed by the site through the hospital or a physician. 
See Section 3.1 about OAP administration. 
f Vital signs include sitting blood pressure and heart rate; body temperature, weight, and height. Height only needs to be recorded at randomization. 
g If 12-lead ECG medically necessary and obtained at any other time, the results need to be recorded. 
h Obtain blood samples for analysis of hematology and blood chemistry by a local certified/accredited laboratory (see Section 9.9). Creatinine and CBC 
must be available from blood draws after TAVI with the patient being clinically stable. CrCL should be calculated by the Cockcroft-Gault formula. 
Normal lab ranges also need to be documented within the eCRF. For Visits 2 and onward. If recent (within 15 days before randomization) lab values 
for blood analyses are available through standard of care, these values may be reported and no new sampling or analyses is required. 
VKA subjects only: INR values and VKA dose are collected (preferably monthly) and entered into the eCRF either during the study visits by local lab 
determination (if they haven’t already been entered). INR values and VKA doses collected through the general practitioner, a local anticoagulation 
clinic, or by the trained and certified patient using a certified device must also be considered and collected. However, this does not constitute a waiver 
for subject’s planned INR determination during study visits. Dose of VKA may need to be adjusted based on these results to maintain INR values 
from 2.0 to 3.0 (numbers inclusive) [Japan: 1.6-2.6 in subjects age ≥70 (numbers inclusive)].Liver function panel will be obtained at Screening 
(unless recent, within the last 15 days, results are available), and at the 6 and 12 Month Visits, unless clinically necessary at other time points. 
i PACT-Q1 and EQ-5D-5L at Randomization, PACT-Q2 and EQ-5D-5L at 3 months and again at either 12 months or at EOT, whichever comes first. 
Forms will be collected by the CRO for uploading into the data system. 
j Antithrombotic regimen compliance is evaluated at each visit/telephone assessment (both by pill count, self-reporting/physician-reporting, subject 
medication log, and for VKA subjects only, by INR values). In case of a suspected study endpoint, an additional assessment for subject compliance to 
the assigned regimen must be performed. 
k Assessment and recording of (S)AEs and suspected clinical events from the signing of the informed consent, and should be reported as soon as site 
personnel learn of the event and be reported within 24h of the Investigator’s/site’s awareness. Endpoint event and AE reporting should occur 
throughout the study and not be restricted to specific visits. If AST or ALT > 3xULN with simultaneous total bilirubin levels > 2xULN is observed, 
then ALP should be determined.  Hospitalization due to cardiovascular events needs to be assessed. 
l When subjects are being transitioned to non-study medications, record the date and time of last administration of study medication, and collect all 
unused study medication. Subjects are transitioned to an approved OAC of the Investigator’s or treating physician’s choice. The Investigator will 
follow the transition strategy in the approved product label. Subjects who prematurely discontinue study OAC are requested to also complete the Post- 
treatment Follow-up Visit according to this schedule (See Section 5.2.1.1.2 and Section 5.2.1.2.2). 


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m EOT may occur at any time (e.g., at subject withdrawal or discontinuation) and will trigger this subject’s Post-treatment Follow-up Visit. 
n Female subject who are of child bearing potential. 
o Female subject who are of child bearing potential. Furthermore, pregnancy tests are carried out whenever there are clinical indications for the 
existence of a pregnancy. 
p All subjects who have taken study medication should be requested to consent for routine follow-up contact at 6-month intervals following termination 
of study drug. This will normally be as a phone contact until the end of the study is determined by the Sponsor. Should the subject choose to not 
receive phone calls, the site may attempt to retrieve this information from viewing the subject’s medical records or public records. 




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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 ≤ 35% (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 regards 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 poor time in therapeutic range (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 or result in death within 24 hours of symptom onset. 
TIA: TIA is defined as an abrupt onset, over minutes to hours, of a 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. 
 
17.1.2. 
TIMI (Non-CABG) 
• Major 
• 
Any intracranial hemorrhage or any clinically overt bleeding, 
(including bleeding evident in imaging studies) associated with a fall of 
hemoglobin (Hb) of ≥ 5g/dL 
• 
Fatal bleed 
• Requiring Medical Attention 
• 
Overt sign of hemorrhage not meeting major or minor bleed 
• 
Requiring intervention 
• 
Leading to or prolonging hospitalization 
• 
Prompting evaluation 


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• Minor 
• 
Any clinically overt bleeding associated with a fall in Hb ≥ 3g/dL but 
< 5 g/dL 
• Minimal 
• 
Any clinically overt bleeding associated with a fall in Hb <3g/dL 
 
17.1.3. 
BARC Bleed Scoring28 
Type 0: no evidence of bleeding 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may 
include episodes leading to self-discontinuation of medical therapy by the patient without 
consulting a healthcare professional 
Type 2: any overt, actionable sign 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 type 3, 4, or 5 but does meet at least one of the following 
criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) 
leading to hospitalization or increased level of care, or (3) prompting evaluation 
Type 3: clinical, laboratory, and/or imaging evidence of bleeding with healthcare 
provider responses 
o Type 3a: any transfusion with overt bleeding; overt bleeding plus Hb 
drop of 3 to < 5 g/dL (provided Hb drop is related to bleed) 
o Type 3b: overt bleeding plus Hb drop ≥ 5 g/dL (provided Hb drop is 
related to bleed); cardiac tamponade; bleeding requiring surgical 
intervention (excluding dental/nasal/skin/hemorrhoid); bleeding 
requiring intravenous vasoactive drugs 
o Type 3c: intracranial hemorrhage (does not include microbleeds or 
hemorrhagic transformation, does include intraspinal); subcategories 
confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed 
compromising vision 
• Type 4: coronary artery bypass graft (CABG)-related bleeding 
o Perioperative intracranial hemorrhage within 48 hours; reoperation 
after closure of sternotomy for the purpose of controlling bleeding; 
transfusion of ≥ 5 U whole blood or packed red blood cells within 48- 
hour period; chest tube output 2 L within a 24-hour period 
• Notes: If a CABG-related bleed is not adjudicated as at least a type 3 severity 
event, it will be classified as not a bleeding event. If a bleeding event occurs 
with a clear temporal relationship to CABG but does not meet type 4 severity 
criteria, it will be classified as not a bleeding event. 


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• Type 5: fatal bleeding 
o Type 5a: probable fatal bleeding; no autopsy or imaging confirmation 
but clinically suspicious 
o Type 5b: definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation 
• BARC fatal bleeding is meant to capture deaths that are directly due to 
bleeding with no other cause.  The time interval from bleeding event to death 
should be considered with respect to likely causality, but there is no specific 
time limit proposed. 
 
17.1.4. 
GUSTO Definitions29 
• Severe or life-threatening 
• 
Intracerebral hemorrhage 
• 
Resulting in substantial hemodynamic compromise requiring 
treatment 
• Moderate 
• 
Requiring blood transfusion but not resulting in hemodynamic 
compromise 
• Mild 
• 
Bleeding not meeting the criteria of moderate or severe 
 
17.2. 
Myocardial Infarction (Varac-2 & ESC/Third Universal) 
Table 17.3: 
Myocardial Infarction (MI) According to the VARC-2 Definitions 
 
Peri-procedural MI (< 72 hours after the index procedure) 
• New ischemic symptoms (e.g. chest pain or shortness of breath), or new ischemic 
signs (e.g., ventricular arrhythmias, new or worsening heart failure, new ST- 
segment changes, hemodynamic instability, new pathological Q-waves in at least 
two contiguous leads, imaging evidence of new loss of viable myocardium or new 
wall motion abnormality) AND 
• Elevated cardiac biomarkers (preferably CK-MB) within 72 hours after index 
procedure, consisting of at least one sample post-procedure with a peak value 
exceeding 15x as the upper reference limit (URL) for troponin or 5x for CK-MB. 
Spontaneous MI (> 72 hours after index procedure) 
Any one of the following criteria: 
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least one value above the 99th percentile URL, together with the evidence of 
myocardial ischemia with at least one of the following: 
o Symptoms of ischemia 






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• 
Stroke – duration of a focal or global neurological deficit >24 h; OR <24 h if available 
neuroimaging documents, a new haemorrhage or infarct; OR the neurological deficit 
results in death 
• 
No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain 
tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences), to 
be determined by or in conjunction with the designated neurologist* 
• 
Confirmation of the diagnosis by at least one of the following: neurologist or neurosurgical 
specialist; neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed 
on clinical grounds alone 
Stroke classification 
• 
Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by 
infarction of the central nervous system tissue 
• 
Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage 
• 
A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or hemorrhagic 
Stroke definitions** 
• 
Disabling stroke: an modified Rankin Scale (mRS) score of 2 or more at 90 days and an 
increase in at least one mRS category from an individual’s pre-stroke baseline 
• 
Non-disabling stroke: an mRS score at <2 at 90 days or one that does not result in an 
increase in at least one mRS category from an individual’s pre-stroke baseline 
Note: Modified Rankin Scale assessments should be made by qualified individuals according 
to a certification process. 
* Patients with non-focal global encephalopathy will not be reported as stroke without unequivocal 
evidence of cerebral infarction-based upon neuroimaging studies (CT scan or brain MRI). 
** Determination of “Disabling/non-disabling stroke” will not be part of adjudication assessment 
 
17.3.2. 
ECASS I Criteria [European Cooperative Acute Stroke Study (ECASS) 
Type Definition 
HI1 
Small petechiae along the margin of the infarct 
HI2 
More confluent petechiae within the infarct but without space-occupying effect 
PH1 
Blood clot not exceeding 30% of the infarct area with some mild space-occupying effect 
PH2 
Blood clots exceeding 30% of the infarct area with significant space-occupying effect 
 
17.4. 
Valve thrombosis 
Any thrombus attached to or near an implanted valve that occludes part of the blood flow 
path, interferes with valve function, or is sufficiently large to warrant treatment. Note 
that valve-associated thrombus identified at autopsy in a patient whose cause of death 
was not valve-related should not be reported as valve thrombosis. 


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17.4.1. 
Assessment of the occurrence of bioprosthetic valve thrombosis is based 
on Mylotte:30 
i. presence of progressive dyspnea or heart failure worsening; 
ii. increase in transaortic mean gradient by ≥ 10 mm Hg, a transaortic 
mean gradient of ≥ 20 mm Hg, thickening of heart valve leaflet 
(HALT) with impaired mobility (HAM) or visualization of 
thrombus formation on the valve; 
iii. visualization of thrombus formation by cardiac computed 
tomography scan; 
iv. complete reversibility after high intensity anticoagulation (e.g., IV 
heparin). 
 
17.5. 
Systemic thromboembolism 
Systemic thromboembolism [non-central nervous system] is defined as abrupt vascular 
insufficiency of an extremity or organ associated with clinical or radiological evidence of 
arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, 
atherosclerosis, instrumentation). In the presence of atherosclerotic peripheral vascular 
disease, diagnosis of embolism to the lower extremities should be made with caution and 
requires angiographic demonstration of abrupt arterial occlusion. 
 
17.6. 
User Guide for EQ-5D-5L 
EQ-5D-5L User Guide. Basic information on how to use the EQ-5D-5L instrument. 
http://www.euroqol.org/about-eq-5d/publications/user-guide.html 
 
17.7. 
Calculation of Creatinine Clearance (CrCL) 
The Cockcroft-Gault formula for the calculation of CrCL will be used in this study. 
Creatinine Clearance 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)] / [72 x serum creatinine (mg/dL)]