Non-Interventional Study on Edoxaban Treatment in Routine Clinical Practice in Patients With Venous Thromboembolism in Europe
Conditions: Venous Thromboembolism
Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

DSE-EDO-05-14-EU, ETNA-VTE-Europe 
Observational Plan, Version 4.0 Date 12 August 2016 
 
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OBSERVATIONAL PLAN 
 
 
ETNA-VTE-EUROPE 
Non-Interventional Study on Edoxaban Treatment  
in Routine Clinical Practice in Patients  
with Venous Thromboembolism in Europe  
 
DSE-EDO-05-14-EU 
 
 
Sponsor/MAH: 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48 
81379 Munich, Germany 
 
 
Version Number:   4.0 
Date of Version: 12 August 2016 
(EU- PAS register number –EUPAS15504) 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Daiichi Sankyo Europe GmbH 
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PASS INFORMATION  
 
Title  
Non-interventional study on Edoxaban Treatment in 
routiNe clinical prActice in patients with Venous 
ThromboEmbolism in Europe (ETNA-VTE-Europe) 
Protocol version identifier  
DSE-EDO-05-14-EU; Version 4.0  
Date of last version of protocol  
12 August 2016  
EU PAS register number 
EUPAS15504 
Active substance  
Edoxaban tosilate (Proposed ATC: B01AF03) 
Medicinal product  
Lixiana®  
Product reference  
EMEA/H/C/002629  
Procedure number 
EMEA/H/C/002629/MEA/007 
Marketing authorisation holder(s) 
Daiichi Sankyo Europe GmbH 
Joint PASS 
No 
Research Question and Objectives  
Primary objective is the analysis of the overall symptomatic 
VTE recurrence rate during an overall observational period 
of 18 months in unselected patients with acute VTE. The co-
primary objective of this study is to collect and evaluate 
real-world safety data on bleeding events, drug related 
adverse events such as liver adverse events, and mortality 
(VTE-related, CV mortality, and all-cause mortality) in 
patients treated with edoxaban.  
 
The results relating to safety and effectiveness of this study 
will be compared with the respective results of other 
anticoagulants obtained from the PREFER in VTE registry. 
This registry uses highly harmonised endpoint definitions 
and will provide comparative data for patients treated with 
Vitamin K Antagonists (VKAs) and NOACs. In addition, 
the data obtained in the randomized Hokusai-VTE trial will 
be used as external comparator for the interpretation of the 
data collected in the unselected population of this study. 
 
The secondary objective is to assess the effect of edoxaban 
on the symptomatic VTE recurrence rate for patients on 
edoxaban, the symptomatic VTE recurrence rate for patients 
who discontinued edoxaban, patient relevant outcomes such 
as strokes (ischaemic and haemorrhagic), systemic embolic 
events (SEE), hospitalisations related to CV condition 
(including VTE related hospitalisation), post-thrombotic 
syndrome (PTS), extent of exposure and compliance to 

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Title  
Non-interventional study on Edoxaban Treatment in 
routiNe clinical prActice in patients with Venous 
ThromboEmbolism in Europe (ETNA-VTE-Europe) 
edoxaban therapy (judged by the investigator), rate and 
reasons of permanent discontinuation of edoxaban. 
The results related to the secondary objective will be 
compared with external databases (PREFER in VTE and 
Hokusai-VTE) in the same way as the data related to 
primary and co-primary objectives. 
 
Subgroup analyses will be performed in predefined patient 
populations for primary and secondary objectives.  
Country (-ies) of study  
Austria, Belgium, France, Germany, Ireland, Italy, The 
Netherlands, Portugal, Spain, Switzerland, United Kingdom 
Authors  
Marketing authorisation holder(s) 
Daiichi Sankyo Europe GmbH  
Zielstattstr. 48 
81379 Munich, Germany 
  
MAH contact person 
 
 
 
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TABLE OF CONTENTS 
1. 
SIGNATURES ............................................................................................... 9 
2. 
LIST OF ABBREVIATIONS....................................................................... 10 
3. 
RESPONSIBLE PARTIES ........................................................................... 13 
3.1. 
Steering Committee ...................................................................................... 16 
3.2. 
Clinical Event Adjudication Committee ....................................................... 18 
3.3. 
List of Participating Sites and Countries ...................................................... 18 
4. 
ABSTRACT ................................................................................................. 19 
5. 
AMENDMENTS AND UPDATES ............................................................. 24 
6. 
MILESTONES ............................................................................................. 25 
7. 
RATIONALE AND BACKGROUND......................................................... 26 
8. 
RESEARCH QUESTION AND OBJECTIVES .......................................... 29 
8.1. 
Primary Objective ......................................................................................... 29 
8.2. 
Secondary Objectives ................................................................................... 29 
9. 
RESEARCH METHODS ............................................................................. 31 
9.1. 
Study Design ................................................................................................. 31 
9.2. 
Setting ........................................................................................................... 31 
9.2.1. 
Participating Sites ......................................................................................... 32 
9.2.2. 
Eligibility Criteria ......................................................................................... 33 
9.2.3. 
Patient Groups .............................................................................................. 34 
9.2.4. 
Schedule ........................................................................................................ 34 
9.2.5. 
Permanent Discontinuation of Edoxaban ..................................................... 35 
9.2.6. 
Early Study Termination ............................................................................... 35 
9.3. 
Variables ....................................................................................................... 36 
9.3.1. 
Exposure Definition ...................................................................................... 36 
9.3.2. 
Safety Measures ............................................................................................ 37 
9.3.3. 
Effectiveness Measures ................................................................................ 39 
9.4. 
Data Sources ................................................................................................. 39 
9.4.1. 
Baseline/Enrolment ....................................................................................... 39 
9.4.2. 
Follow-up ...................................................................................................... 42 
9.4.3. 
Adverse Drug Reaction Reporting ................................................................ 43 
9.4.4. 
Edoxaban Treatment Discontinuation .......................................................... 43 

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9.4.5. 
Final Assessment .......................................................................................... 43 
9.5. 
Study Size ..................................................................................................... 44 
9.6. 
Data Management (DM) ............................................................................... 44 
9.6.1. 
Data Entry/Electronic Data Capture ............................................................. 45 
9.6.2. 
Source Documents ........................................................................................ 45 
9.6.3. 
File Retention and Archiving........................................................................ 45 
9.7. 
Data Analysis ................................................................................................ 45 
9.7.1. 
Overview on planned analyses ..................................................................... 45 
9.7.2. 
Overview on the statistical methodology ..................................................... 47 
9.7.3. 
Analysis of primary endpoint ....................................................................... 48 
9.7.4. 
Analysis of secondary endpoints .................................................................. 50 
9.8. 
Quality Control ............................................................................................. 52 
9.9. 
Limitations of the Research Methods ........................................................... 53 
9.10. 
Other aspects ................................................................................................. 55 
10. 
PROTECTION OF HUMAN SUBJECTS ................................................... 56 
10.1. 
Review by Ethics Committees/Competent Authorities ................................ 56 
10.2. 
Insurance and Liability ................................................................................. 56 
10.3. 
Patient Information, Informed Consent ........................................................ 56 
10.4. 
Data Protection ............................................................................................. 56 
10.5. 
Numbering and Identification of Patients ..................................................... 57 
10.6. 
Assessments .................................................................................................. 57 
11. 
MANAGEMENT AND REPORTING OF ADVERSE DRUG 
REACTIONS ................................................................................................ 58 
11.1. 
Definitions .................................................................................................... 58 
11.2. 
Reporting of Suspected ADRs by the Investigator ....................................... 59 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ..................................................................................................... 60 
13. 
DOCUMENTATION AND ARCHIVING .................................................. 61 
14. 
LEGAL REQUIREMENTS ......................................................................... 62 
14.1. 
Reimbursement ............................................................................................. 62 
14.2. 
Registration ................................................................................................... 62 
15. 
FINAL REPORT .......................................................................................... 63 
16. 
PUBLICATION ............................................................................................ 64 

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17. 
PREMATURE TERMINATION OF THE PASS ........................................ 65 
18. 
REFERENCES ............................................................................................. 66 
APPENDIX 1. LIST OF STAND-ALONE DOCUMENTS ........................................ 67 
APPENDIX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ......................... 68 
 
 
 
 
 

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LIST OF TABLES 
Table 1: 
Voting members of the Steering Committee and National Coordinators 
(members of the executive board are marked with an asterisk) ................... 17 
Table 2: 
Non-voting members of the Steering Committee ......................................... 17 
Table 3: 
Amendments and updates of the observational plan (version 1.0, dated 20 
Feb 2015) ...................................................................................................... 24 
Table 4: 
Main study milestones .................................................................................. 25 
Table 5: 
Data Collection Flow Chart .......................................................................... 41 
 
 
 
 

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LIST OF FIGURES 
Figure 1: 
Overview study flow ..................................................................................... 25 
Figure 2: 
Study schedule .............................................................................................. 35 
 
 
 
 
 
 

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2. 
LIST OF ABBREVIATIONS 
 
ADR 
 
Adverse Drug Reaction 
AF 
 
Atrial Fibrillation 
ALT 
 
Alanine Transaminase 
AST 
 
Aspartate Transaminase 
BMI 
 
Body Mass Index 
BL 
 
Baseline 
CA 
 
Competent Authority 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CHADS2 
 
Risk factor score [derived from cardiac failure, hypertension, age, 
diabetes, stroke (doubled)] 
CHA2DS2-VASc 
Risk factor score [derived from cardiac failure, hypertension, age 
≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65–
74 and sex category (female)] 
CHD 
 
Coronary Heart Disease 
CI 
 
Confidence Interval 
COP 
 
Clinical Operations Plan 
CrCl 
 
Creatinine Clearance 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organisation 
CSPV 
 
Clinical Safety and Pharmacovigilance 
CV 
 
Cardiovascular 
DACH 
 
Acronym for the region consisting of Germany, Austria and 
Switzerland 
DB 
 
Database  
DM 
 
Data Management 
DS 
 
Daiichi Sankyo 
DSE 
 
Daiichi Sankyo Europe GmbH 
DVT 
 
Deep Vein Thrombosis 
ECG  
 
Electrocardiogram 
eCRF 
 
Electronic Case Report Form 
EDC 
 
Electronic data capture 

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EMA 
 
European Medicines Agency 
FPI 
 
First Patient In 
FU 
 
Follow Up 
FXa 
 
Factor Xa 
GPP 
 
Good Pharmacoepidemiology Practice 
GVP 
 
Good Pharmacovigilance Practice  
HAS-BLED  
Score for assessment of bleeding risk [hypertension, abnormal 
renal/liver function, stroke, bleeding history or predisposition, labile 
INR, elderly (>65), drugs/alcohol concomitantly] 
ICF 
 
Informed Consent Form 
ICH 
 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use  
ICU 
 
Intensive Care Unit 
ID 
 
Identification Number 
IEC 
 
Independent Ethics Committee 
INR 
 
International Normalised Ratio 
IPL 
 
International Project Leader 
LPI 
 
Last Patient In 
LPO 
 
Last Patient Out 
LSO 
 
Local safety officer 
MAH 
 
Marketing Authorisation Holder 
MI 
 
Myocardial Infarction 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
NOAC 
 
Non-Vitamin K Oral Anticoagulant 
NC 
 
National Coordinator 
NIS  
 
Non-interventional Study 
NVAF 
 
Non-Valvular AF 
OAC 
 
Oral Anticoagulant 
PASS  
 
Post-Authorisation Safety Study 
PE 
 
Pulmonary Embolism 
PRAC 
 
Pharmacovigilance Risk Assessment Committee 
PREFER in VTE 
Prevention of Thromboembolic Events – European Registry in 
Venous Thromboembolism 

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pSOC 
 
Primary System Organ Class (MedDRA) 
PT 
 
Preferred Term (MedDRA) 
PTS 
 
Post-thrombotic syndrome 
SADR 
 
Serious Adverse Drug Reaction 
SAP 
 
Statistical Analysis Plan 
SC 
 
Steering Committee 
SAS® 
 
Statistical Analysis Software 
SDTM 
 
Study Data Tabulation Model (CDISC) 
SEE 
 
Systemic Embolic Event 
SmPC 
 
Summary of Product Characteristics 
SOP 
 
Standard Operating Procedure 
TMF 
 
Trial Master File 
TIA 
 
Transient Ischemic Attack  
VKA 
 
Vitamin K Antagonist 
VTE 
 
Venous Thromboembolism 
 
 
 
 

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3. 
RESPONSIBLE PARTIES 
 
Senior International Project Leader  
Daiichi Sankyo Europe GmbH 
 
 
 
 
 
 
Chair of Steering Committee 
 
 
 
 
 
European Qualified Person for 
Pharmacovigilance  
Daiichi Sankyo Europe GmbH 
 
Safety Physician 
Daiichi Sankyo Europe GmbH 
 
 
 
 
Head of Antithrombotics & 
Cardiovascular  
Daiichi Sankyo Europe GmbH 
 
 
 
 
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Study Data Manager 
Daiichi Sankyo Europe GmbH 
 
 
 
 
 
 
Study Statistician 
Daiichi Sankyo Europe GmbH 
 
 
 
 
 
 
 
Contract Research Organisation  
Project Leader  
Responsible for the conduct of the study 
in the Switzerland, Austria, Belgium, 
Ireland, The Netherlands and the United 
Kingdom and for overall Data 
Management, Biostatistics and Medical 
Writing 
Quintiles Switzerland Sàrl 
Real-World Late Phase Research 
 
 
 
Contract Research Organization  
Project Leader 
Responsible for the conduct of the 
study in Germany  
 
 
 
Contract Research Organisation  
Project Leader  
Responsible for the conduct of the study 
in France 
SSS International Clinical Research GmbH 
ITEC Services 
 
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Contract Research Organisation  
Project Leader  
Responsible for the conduct of the study 
in Italy 
Hippocrates Research S.r.l. 
 
 
 
Contract Research Organisation  
Project Leader 
Responsible for the conduct of the study 
in Spain and Portugal  
IMS Health 
 
Contract Research Organisation  
Adjudication Coordinator  
Responsible for Coordinating the Event 
Adjudication 
IPPMed GmbH 
 
 
 
 
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3.1. 
Steering Committee  
The Steering Committee (SC) is the primary group with supervisory responsibility for all aspects 
of the conduct of this non-interventional PASS in venous thromboembolism (DSE-EDO-05-14-
EU). It is contributing to the design of the study, ensuring the maintenance of the scientific quality 
and integrity of conduct and will support the team in all study related aspects during the run of the 
study. The SC will evaluate the results together with the Daiichi Sankyo Project Team and will 
review the study report as well as publications based on the results of the PASS.  
The SC consists of external renowned members of the scientific community with a strong medical 
background in the treatment of VTE and specialists in health economics, biostatistics and 
epidemiology. Each country will contribute at least one member to the SC. The responsibilities of 
the SC are: 
- 
Participation in Steering Committee meetings 
- 
Scientific and medical advice prior, during and after the study, including evaluation and 
interpretation of the results of the study 
- 
Advice in observational plan and electronic case report form (eCRF) development 
- 
Support the performance of the study as a contact person for sites and other personnel 
involved in the study (act as National Coordinating site for the country) 
- 
Chair and lead local meetings in local language in the corresponding country, if deemed 
necessary 
- 
Provide scientific and medical advice regarding the PASS results  
- 
Reconciliation of safety and efficacy outcomes 
- 
Support and advice on publication, abstracts, posters, journals and congresses in 
connection with the study.  
To facilitate and drive decisions there will be an executive board that will meet more frequently. 
In addition, four selected persons of the Daiichi Sankyo Project Team have been assigned as 
Steering Committee members from the following functions: Medical Affairs, Late Phase Clinical 
Operations and Real World Evidence, Clinical Safety and Pharmacovigilance, Biostatistics. These 
members will participate in the meetings as non-voting members. Members are displayed in Table 
1 and Table 2. 
 
 
 

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Table 1: 
Voting members of the Steering Committee and National Coordinators 
(members of the executive board are marked with an asterisk) 
Chair 
 
Guy's and St Thomas' NHS Foundation Trust, 
King's College London, United Kingdom 
SC*, 
NC 
Italy 
 
University of Perugia, Santa Maria della 
Misericordia Hospital  
SC*, 
NC 
Austria 
 
Medical University of Vienna 
SC, 
NC 
Belgium 
 
Cliniques Universitaires Saint-Luc, Bruxelles 
SC, 
NC 
France 
 
Centre Hospitalier Universitaire de Saint-
Etienne  
SC*, 
NC 
Germany 
 
Hospital of the Ludwig-Maximilians-
University (LMU) Munich 
SC*, 
NC 
Ireland 
 
Mater Hospital, Dublin 
SC, 
NC 
The 
Netherlands 
 
Academisch Medisch Centrum, Amsterdam 
SC, 
NC 
Portugal 
 
Hospital Santa Marta, Lisbon 
SC, 
NC 
Spain 
 
Ramón y Cajal Hospital, Madrid 
SC*, 
NC 
Switzerland 
 
University Hospital Zurich 
SC, 
NC 
Health 
Economy 
 
Boston Healthcare Associates International 
GmbH, Steinbeis-University, Berlin, 
Germany 
SC* 
Health 
Economy 
 
LEDa – LEGOS, Université Paris – 
Dauphine, France 
SC 
Health 
Economy 
 
Universidad Castilla-La Mancha, Toledo, 
Spain 
SC 
Statistics 
 
Hôpital Fernand Widal, Paris, France 
SC* 
 
Table 2: 
Non-voting members of the Steering Committee 
Late Phase Clinical Operations and Real World Evidence 
 
 
Biometrics  
 
 
Medical Affairs 
 
 
Clinical Safety and Pharmacovigilance  
 
 
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3.2. 
Clinical Event Adjudication Committee 
Events of special importance (recurrent VTE, major bleedings, and deaths) will be adjudicated by 
an independent clinical event adjudication committee. Assessment will be made by consensus. The 
scope and process will be described in a separate Event Adjudication Committee Charter. 
 
3.3. 
List of Participating Sites and Countries 
A list of the principal investigators and all collaborating institutions is kept in a stand-alone 
document and can be made available upon request. For planned sites and patient numbers refer to 
Section 9.2.1. 
It is planned to include 2,700 patients from approximately 660 sites in up to 11 European countries 
[Austria, Belgium, France, Germany, Ireland, Italy, The Netherlands, Portugal, Spain, Switzerland 
and United Kingdom]. 
 
 
 
 

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4. 
ABSTRACT 
 
Study Title 
Non-interventional study on Edoxaban Treatment in routiNe clinical 
prActice in patients with Venous ThromboEmbolism in Europe 
(ETNA-VTE-Europe) 
Protocol Version 
Identifier 
DSE-EDO-05-14-EU 
Version 4.0 
Date of Protocol Version 
12 August 2016  
Marketing Authorisation 
Holder (MAH) 
Daiichi Sankyo Europe GmbH (DSE) 
Zielstattstr. 48 
81379 Munich, Germany 
Main Authors 
 IPL 
Daiichi Sankyo Europe GmbH 
Rationale and 
Background 
Edoxaban is an orally administered anticoagulant that inhibits 
coagulation factor Xa. It has been recently approved by the European 
Medical Agency (EMA) for use in adult patients for the treatment of 
acute venous thromboembolism (VTE) including deep vein 
thrombosis (DVT) and/or pulmonary embolism (PE), and prevention 
of recurrent VTE in adults.  
According to current guidelines, duration of anticoagulant treatment 
after a venous thromboembolic event varies from 3 months to 
indefinite treatment depending on the estimated risks of venous 
thromboembolism (VTE) recurrence and bleeding. Current data for 
edoxaban are limited to a maximum treatment duration of 12 months 
(Hokusai-VTE; N Engl J Med. 2013; 369:1406-15).  
Therefore, this study aims to gather further insight into efficacy (i.e. 
symptomatic recurrent VTE) and safety (i.e. bleeding events, liver 
adverse events, all-cause mortality and other drug related adverse 
events) of extended treatment with edoxaban up to 18 months in an 
unselected patient population in routine clinical practice. 
Research Question and 
Objectives 
Primary Objective: 
 
Primary objective is the analysis of the overall symptomatic 
VTE recurrence rate during an overall observational period of 
18 months in unselected patients with acute VTE.  
 
The co-primary objective of this study is to collect and evaluate 
real-world safety data on bleeding events, drug related adverse 
events such as liver adverse events, and mortality (VTE-related, 
CV mortality, and all-cause mortaility) in patients treated with 
edoxaban. 
 
The results relating to safety and effectiveness of this study will be 
compared with the respective results of other anticoagulants obtained 
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from the PREFER in VTE registry. This registry uses highly 
harmonised endpoint definitions and will provide comparative data 
for patients treated with Vitamin K Antagonists (VKAs) and 
NOACs. In addition, the data obtained in the randomized Hokusai-
VTE trial will be used as external comparator for the interpretation 
of the data collected in the unselected population of this study. 
 
Secondary Objectives:  
To assess the effect of edoxaban on the:  
 
symptomatic VTE recurrence rate for patients on edoxaban 
 
symptomatic VTE recurrence rate for patients who permanently 
discontinued edoxaban 
 
patient relevant outcomes such as strokes (ischaemic and 
haemorrhagic), systemic embolic events (SEE), 
 
hospitalisations related to CV condition (including VTE related 
hospitalisation), post-thrombotic syndrome (PTS) 
 
extent of exposure and compliance to edoxaban therapy (judged 
by the investigator), rate and reasons of permanent 
discontinuation of edoxaban  
The results related to the secondary objective will be compared with 
external databases (PREFER in VTE and Hokusai-VTE) in the same 
way as the data related to primary and co-primary objectives. 
 
Subgroup analyses will be performed in predefined patient 
populations for primary and secondary objectives.  
Study Design  
Multinational, multicentre, prospective, non-interventional post-
authorisation safety study (PASS). 
Patients from different countries and care settings will be enrolled 
and followed up for 18 months. 
Population 
Setting 
Patients from different countries and care settings (primary care and 
secondary care, different specialities) to ensure representativeness 
and extended assessment is planned for collection of VTE 
recurrences for up to 18 months after last data collection point for 
patients who entered the PASS early. 
 
Period of patient recruitment: 2 years per country  
 
Documentation of baseline and follow up information at 1, 3, 6, 
12, and 18 months (only when available). In addition, 
recurrence of symptomatic VTE and death will be captured 
retrospectively at time point of Last Patient Out per country  

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 
Patients who discontinue permanently edoxaban during the 
observational period will be followed up according to the same 
scheme  
 
Electronic data capture (EDC) 
 
Sites and Countries 
 
About 660 sites including hospitals and office-based sites in up 
to 11 European countries [Austria, Belgium, France, Germany, 
Ireland, Italy, The Netherlands, Portugal, Spain, Switzerland 
and United Kingdom]. 
 
Study Population 
 
Approximately 2,700 patients with acute VTE  
Inclusion/exclusion 
criteria 
 
Established acute initial or recurrent VTE 
 
Patients treated with edoxaban according to Summary of 
Product Characteristics (SmPC). To ensure that the physician’s 
prescribing behaviour will not be influenced, patients may only 
be included after the treating physician has made the clinical 
decision to prescribe edoxaban  
 
Written informed consent for participation in the study (ICF) 
 
Not simultaneously participating in any interventional study 
Variables 
(Observation Criteria) 
Parameters recorded during the observational period: 
Patient characteristics (demography,  medical history, 
history/diagnosis and current status of VTE, PTS assessment (will be 
collected in specific centres only) risk factors, comorbidities, 
concomitant medication, previous interventions) 
Clinical outcome 
Efficacy: (symptomatic recurrent VTE (i.e. the composite of DVT, 
non-fatal PE, and fatal PE), strokes (ischaemic and haemorrhagic), 
systemic embolic events (SEE)), hospitalisations related to CV 
condition (including VTE related hospitalisation)  
Safety: bleeding (major bleeding events including intracranial 
haemorrhage, clinically relevant non-major bleeding events, minor 
bleeding events), suspected edoxaban related adverse events will be 
collected and coded using the standardized Medical Dictionary for 
Regulatory Activities (MedDRA)) 
Mortality: VTE related mortality CV mortality, all-cause mortality. 
Laboratory values (as available in medical records* - e.g. aspartate 
transaminase (AST), alanine transaminase (ALT), bilirubin, 
creatinine, creatinine clearance (CrCl)) 

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(*) physicians will not be required to perform any mandatory 
laboratory assessment 
Use pattern of edoxaban in VTE (documentation of therapy, dosage, 
prescription intervals, dose adjustments, discontinuations, switches 
and reasons for these, concomitant medication, additional 
therapy/interventions, physician judgment on the compliance to 
edoxaban.  
Data Sources 
As this is a non-interventional study, only data on clinical routine 
practice will be documented. To facilitate accurate recording of data, 
patients can optionally fill in a memory aid to note important details. 
Study Size 
Sample size justification with respect to primary objective: 
The overall recurrence rate of symptomatic VTE during the 18-
month observation period is assumed to be 8.0 % (0.08).* Assuming 
furthermore a relative precision of 15% (i.e. an absolute precision of 
1.2% resp. 0.012), for a two-sided 95%-confidence interval at least 
1,964 patients are needed. Given a drop-out-rate of 25%, it will be 
sufficient to enroll approx. 2,700 patients into the study. 
*The assumed rate refers to all patients regardless of the fact whether 
they stopped treatment with edoxaban during the 18 months or not. 
  
Sample size considerations with respect to co-primary objective: 
For the co-primary objective, i.e. to collect and evaluate real-world 
safety data, the intention is to use a data pool as large as possible. 
Therefore, the safety data of this PASS (ETNA-VTE-Europe, DSE-
EDO-05-14-EU) is combined with the safety data of a parallel 
edoxaban PASS (ETNA-AF-Europe, DSE-EDO-04-14-EU) which 
allows the total dataset to be in line with the presentation of the 
safety profile in the European SmPC. ETNA-AF-Europe is 
conducted in non valvular atrial fibrillation (NVAF) patients and is 
planned to recruit 13,100 patients. In both studies a combined total 
of 15,800 patients shall be recruited. Assuming a drop-out rate of 
20% within the first 18 months, 12,640 patients should be evaluable 
for the estimation of the 95% confidence intervals of the incidence 
rates of interest (e.g. bleeding, mortality, adverse drug reactions) 
after 18 months. For uncommon adverse drug reactions (i.e. 
incidence rates between 0.1% and 1%), the 95% CIs will be 
estimated taking the actual number of patients into account. For the 
assumed number of 12,640 patients from the combined safety 
databases, the 95% CI will have a precision ranging from ± 0.06% 
for an incidence rate of 0.1% to ± 0.17% for an incidence rate of 1%. 
The power will be sufficient to capture uncommon adverse drug 
reactions with low incidence rates. 
Data Analysis 
For the final analysis of the safety data, two analyses are planned:  
 
Final analysis based on the data of the ETNA-VTE-Europe 
(including the comparison to the corresponding results of the 

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PREFER in VTE (disease registry) as well as to the results of 
the Hokusai-VTE study (clinical trial)) 
 
Combined safety analysis of ETNA-AF-Europe and ETNA-
VTE-Europe based on the 18-month safety data of both studies.  
 
Data snapshots are planned on a yearly basis. (First data snapshot is 
planned in Q1 2018). 
 
Details of the data analysis strategy will be fully described in the two 
respective Statistical Analysis Plans (SAPs).  
 
Binary, categorical, and ordinal parameters will be summarised by 
means of absolute and relative (percentage) frequencies within the 
various categories. Continuous parameters will be summarised by 
means of standard descriptive summary statistics. In addition, 
adequate graphs (e.g. bar charts, box-whisker plots) will be 
presented. Kaplan-Meier plots will be generated where applicable to 
characterize the risk over time for each outcome. Time-to-event 
parameters will be analysed by means of Cox proportional hazard 
regression model to compare the pre-defined sub-populations. The 
purpose of all analyses will not be confirmatory but purely 
descriptive/ exploratory.  
Quality Control 
This study will be conducted according to the rules of Good 
Pharmacoepidemiology Practice (GPP) and the ‘Guideline on Good 
Pharmacovigilance Practices (GVP) – Module VIII (Rev 1)’ 
EMA/813938/2011 Rev 1. Related quality control mechanisms (e.g. 
data plausibility checks, monitoring of data) will be performed 
accordingly. 
Milestones  
First Patient In (FPI)/Start of data collection: Q4 2016 
Last Patient Out (LPO)/End of data collection: Q4 2020  
Interim reports: Regular interim status reports, annual data 
snapshots, pooled safety analysis after 18 months of follow up 
(combined with ETNA-AF-Europe)  
Final report: Q3 2021 
 
 

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5. 
AMENDMENTS AND UPDATES 
This is the revised protocol according to the questions and comments received after review of the 
PRAC (see Table 3). In case of essential changes of the observational plan the investigators will 
be informed as well as the respective competent authorities and Independent Ethics Committees 
as required by local laws or regulations. 
 
Table 3: 
Amendments and updates of the observational plan (version 1.0, dated 20 
Feb 2015) 
No 
Date 
Section of study 
protocol 
Amendment or update 
Reason 
1 
30 Nov 2015 
Full protocol 
Amendment to V 1.0; New 
version 2.0 
PRAC request 
2 
11 May 2016 
Full protocol 
Amendment to V 2.0; 
New version 3.0 
PRAC request  
3 
12 August 2016 
Full protocol 
Amendment to V 3.0; 
New version 4.0 
PRAC request  
 
 

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7. 
RATIONALE AND BACKGROUND 
Venous Thromboembolism (VTE) 
VTE is the third most common cardiovascular disease after myocardial infarction (MI) and stroke.1 
Often occurrence of VTE can be attributed to various risk factors such as immobilisation, trauma, 
cancer, obesity and hereditary or acquired thrombophilia. The incidence of VTE is approximately 
1-2 per 1,000 of the population with incidence increasing with age. It is estimated that 1 in 20 
people will have a VTE at some point in their life and approximately half the cases are associated 
with prior hospitalisation for medical illness or surgery. VTE can be categorized as idiopathic 
(primary, unprovoked) and as provoked (secondary). Patients with idiopathic VTE are much more 
likely to suffer a recurrent event than those with secondary VTE after discontinuation of 
anticoagulation.  
Detailed estimates of the annual number of VTE events are hard to obtain since VTE is often 
asymptomatic and difficult to diagnose, resulting in a marked underestimation of VTE incidence. 
The VTE Impact Assessment Group in Europe designed an incidence-based model to estimate the 
total annual number of non-fatal incident and recurrent VTE events as well as the VTE-related 
deaths in France, Germany, Italy, Spain, Sweden and UK.2 For the year 2004, a total of 761,697 
non-fatal VTE events and 370,012 VTE-related deaths were estimated to have occurred across 
these six EU countries. This highlights the importance of implementing appropriate strategies for 
prevention and treatment of VTE. 
 
Edoxaban 
Edoxaban has been approved by the U.S. Food and Drug Administration FDA, Swissmedic and 
by the European Medical Agency (EMA). 
In the EU it is approved for the following indications: 
 Prevention of stroke and systemic embolism in adult patients with NVAF with one or 
more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, 
diabetes mellitus, prior stroke or transient ischemic attack (TIA).  
 Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and 
prevention of recurrent DVT and PE in adults. 
 
The approval is based on the following pivotal studies: 
The ENGAGE AF-TIMI 48 trial was a multinational, randomised, double-blind, double-dummy, 
non-inferiority study comparing the efficacy and safety of two dosing regimens of once-daily 
edoxaban to dose-adjusted warfarin (target international normalised ratio [INR] 2.0 to 3.0) in adult 
patients (N=21,105) with non-valvular AF at moderate-to-high risk of stroke.3,4 Patients 
randomised to the edoxaban once-daily group received high dose 60 mg or low dose 30 mg (with 
50% dose reduction in each dose group for patients with moderate renal impairment, low body 
weight, or concomitant P-gp inhibitor use). Among the exclusion criteria was the presence of 
conditions associated with high risk of bleeding such as overt gastrointestinal bleeding or active 

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ulcer within the previous year or if patients were receiving medications that increased the risk of 
bleeding. 
The primary efficacy endpoint was the time to the first adjudicated stroke (ischaemic or 
haemorrhagic) or systemic embolic event. The median duration of treatment exposure was 
approximately 2.4 years and the median follow-up was 2.8 years. The median time in the 
therapeutic range (TTR) in the warfarin group was 68.4%.3,4 
Both high-dose edoxaban (60 mg or dose-reduced 30 mg [60/30 mg]) and low-dose edoxaban (30 
mg or dose-reduced 15 mg [30/15 mg]) once-daily were non-inferior to well-controlled warfarin 
for the prevention of stroke or systemic embolism in patients with AF, with a 21% reduction in 
risk in the high-dose edoxaban (60/30 mg) arm (p<0.001 for non-inferiority). 
An analysis of ischaemic stroke found a similar event rate between the high-dose edoxaban (60/30 
mg) and warfarin arms but a significantly higher rate in the low-dose edoxaban (30/15 mg) arm 
than in the warfarin arm (absolute rate increase 41%; p<0.001 vs. warfarin). This unfavourable 
outcome for ischaemic stroke for the 30/15 mg dose led to the selection of the 60/30 mg dose for 
the regulatory submissions to FDA and EMA. 
The Hokusai-VTE study (N=8,292) in patients with symptomatic VTE had a flexible treatment 
duration of 3–12 months and found that following initial heparin, edoxaban 60 mg once daily was 
non-inferior to dose-adjusted warfarin (INR 2.0–3.0) for the prevention of recurrent VTE, and also 
had a significantly lower risk for the composite of major or non-major clinically relevant bleedings 
(primary safety outcome).5, 6 
According to current guidelines, duration of anticoagulant treatment after a venous 
thromboembolic event varies from 3 months to indefinite treatment depending on the estimated 
risks of venous thromboembolism (VTE) recurrence and bleeding. Current data for edoxaban are 
limited to a maximum treatment duration of 12 months.5  
 
Rationale 
In order to understand the risks and benefits of edoxaban use in a real-world clinical setting, 
Daiichi-Sankyo introduced this PASS (ETNA-VTE-Europe) as part of the Risk Management Plan 
of edoxaban to gain insight into efficacy (i.e. symptomatic recurrent VTE) and safety (i.e. bleeding 
events including intracranial haemorrhage, drug related adverse events such as liver adverse 
events, hospitalisation related to cardiovascular (CV) condition (including VTE related 
hospitalisations), CV and all-cause mortality of VTE patients) of treatment with edoxaban up to 
18 months in an unselected patient population in routine clinical practice. 
Real-world evidence data in routine clinical practice use of edoxaban up to 18 months will be 
collected in 2,700 patients, treated by specialized as well as non-specialized physicians in hospitals 
and office based centres.  
 
For designing ETNA-VTE-Europe, the PREFER in VTE as well as the RIETE registry were taken 
into consideration.  

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The PREFER in VTE disease registry (Prevention of Thromboembolic Events –European 
Registry in Venous Thromboembolism)7 was a prospective, observational, multicentre disease 
registry conducted in seven European countries to assess the characteristics and the management 
of patients with VTE, by investigating the safety and efficacy. In addition, the use of health care 
resources, as well as the costs for 12 months treatment following a first-time and/or recurrent VTE 
diagnosed in hospitals or specialized or primary care centres was part of the assessment. Three 
hundred and eighty one centres participated, which enrolled 3,464 patients with an acute event at 
the time of enrolment. Patients were eligible to be enrolled into the registry if they were at least 18 
years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as 
either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline 
data collection point at the time of the acute VTE event, further follow-up documentations 
occurred at 1, 3, 6 and 12 months.  
The RIETE registry, an ongoing, international, multicentre, prospective cohort of consecutive 
patients presenting with symptomatic venous thromboembolism (deep-vein thrombosis, PE, or 
both) was explored by the MAH.8 RIETE is the largest ongoing registry, using a similar design 
(non-interventional, non-randomized single arm trial) with a large sample size (n~ 43,000) and 
investigating the same objective, namely the safety and efficacy of patients with acute VTE treated 
with an anticoagulant.7,8 
 
Thus, real-world evidence data in routine clinical practice use of edoxaban up to 18 months will 
be collected in 2,700 patients, treated by specialized as well as non-specialized physicians in 
hospitals and office based centres. The single-arm approach without a comparator group was 
chosen as patient profiles between treatment arms differ in a non-randomized, non-interventional 
setting. As a comparator group is nevertheless useful to understand the results obtained and in 
order to put the results into the right perspective, the results gained in ETNA-VTE-Europe will be 
compared to data from the PREFER in VTE disease registry. The PREFER registry, was selected 
as it is similar in bleeding definition, comparable in data collection point schedules, with a robust 
number of patients (~3,500 patients) enrolled.  
As the PREFER in VTE enrolled patients treated with different oral anticoagulants, analysis on 
different treatments can be conducted (e.g. NOACs, VKA, and heparin alone or on combinations 
for Europe and per country). In addition, several subgroup analyses (renal impaired, hepatic 
impaired patients) can be performed based on the data from the PREFER in VTE.  
The PREFER database will allow a meaningful comparison of the data collected in ETNA-VTE-
Europe. Furthermore, the results obtained in the ETNA-VTE-Europe will be put in relation to the 
results of the Hokusai VTE study.  
 

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8. 
RESEARCH QUESTION AND OBJECTIVES  
In order to understand the risks and benefits of edoxaban use in a clinical setting close to ‘real-
world’, Daiichi-Sankyo introduced this non-interventional post-authorization safety study (PASS) 
as part of the Risk Management Plan of edoxaban to gain insight into the efficacy (overall 
symptomatic VTE recurrence rate) and safety (bleeding events including intracranial 
haemorrhage, drug related adverse events such as liver adverse events, hospitalisation related to 
cardiovascular (CV) conditions including VTE related hospitalization, VTE related, CV mortality 
and all-cause mortality in VTE patients) in non-preselected patients with VTE treated with 
Edoxaban. 
 
8.1. 
Primary Objective  
Primary objective is the analysis of the overall symptomatic VTE recurrence rate during an overall 
observational period of 18 months in unselected patients with acute VTE.  
 
The co-primary objective of this study is to collect and evaluate real-world safety data on bleeding 
events, drug related adverse events such as liver adverse events, and mortality (VTE-related, CV 
mortality, and all-cause mortality) in patients treated with edoxaban. 
 
The results relating to safety and effectiveness of this study will be compared with the respective 
results of other anticoagulants obtained from the PREFER in VTE registry. This registry uses 
highly harmonised endpoint definitions and will provide comparative data for patients treated with 
Vitamin K Antagonists (VKAs) and NOACs. In addition, the data obtained in the randomized 
Hokusai-VTE trial will be used as external comparator for the interpretation of the data collected 
in the unselected population of this study. 
 
8.2. 
Secondary Objectives 
Secondary objectives are to assess the effect of edoxaban on the 
 symptomatic recurrence rate of VTE for patients on edoxaban and  
 symptomatic recurrence rate of VTE for patients who permanently discontinued 
edoxaban 
 patient relevant outcomes such as strokes (ischaemic and haemorrhagic), systemic 
embolic events (SEE), post-thrombotic syndrome (PTS) 
 Hospitalisations related to CV conditions (including VTE related hospitalisation) 
 extent of exposure and compliance to edoxaban therapy, rate and reasons of 
permanent discontinuation of edoxaban 
 

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The results related to the secondary objective will be compared with external databases (PREFER 
in VTE and Hokusai-VTE) in the same way as the data related to primary and co-primary 
objectives. 
 
In addition, subgroup analyses will be performed in the predefined patient populations (see 
Section 9.7.3). Furthermore, primary and secondary objectives will be presented for all patients 
that permanently discontinue edoxaban. 
 

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9. 
RESEARCH METHODS 
9.1. 
Study Design 
This study is an European, multicentre, prospective, non-interventional post-authorisation safety 
study. This PASS is conducted to evaluate the effectiveness and safety in patients with acute VTE 
treated with edoxaban in up to 11 European countries (Austria, Belgium, France, Germany, 
Ireland, Italy, Portugal, Spain, Switzerland, The Netherlands, United Kingdom). Patients from 
different countries and care settings (primary care and secondary care, different specialities) will 
be enrolled to ensure representativeness. An extended follow up is planned for collection of VTE 
recurrences for up to 18 months. In addition, recurrence of symptomatic VTE and death will be 
captured retrospectively at time point of Last Patient Out (LPO) per country. 
 
9.2. 
Setting 
Edoxaban is currently approved for use in adult patients for the treatment of acute first time (initial) 
or recurrent VTE including DVT and/or PE, and prevention of recurrent VTE in adults.  
Treatment pattern, treatment initiation, continuation or changes to edoxaban are solely at the 
discretion and responsibility of the physician and the patient. In order to ensure that the prescribing 
patterns of any individual treating physician is not influenced, patients may only be included in 
the study after the treating physician has made the clinical decision to prescribe edoxaban. All 
medication will be prescribed according to the usual standard of care and will not be provided by 
the study sponsor. Participation in the study will in no way influence payment or reimbursement 
for any treatment received by patients during the study. No study specific data collection points 
are to be performed. 
Patients from different countries and care settings will be enrolled and followed up for 18 months. 
A two-year patient recruitment period per country is planned. 
The overall number of patients per site and the number of sites per country may be adjusted during 
the study to meet enrolment goals, if needed. To the extent possible, consecutive patients meeting 
inclusion/exclusion criteria will be enrolled. In order to make sure that a sufficient number of sites 
and patients will be involved in the study, a comprehensive contingency plan is put in place as part 
of the Recruitment Strategy Plan. 
Patients should be included in the study within two weeks after start of the acute VTE event. All 
efficacy and safety related events will be retrospectively documented beginning with the first 
heparin administration. At baseline, the relevant patient history will be recorded including VTE-
related events. Furthermore, the current status of the patient will be recorded.  
After baseline assessment, data will be documented approximately at 1, 3, 6, 12 and 18 months at 
the site. The proposed follow up visits are data collection points only that are in line with the 
clinical routine in all participating countries. Patients will not be invited for any study specific 
reasons and are not obliged to return according to the planned schedule for data documentation. 
The proposed data collection points are voluntarily and do not interfere with the daily practice. 
Patient visits to the treating physician will only occur in line with clinical routine in the 
participating countries and not for study purposes. 

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If possible, patients who permanently discontinue treatment with edoxaban will be followed up 
according to the same scheme. In case investigators are not able to see the patient again at the 
follow up data collection point, investigators can follow up the patients via phone if this procedure 
is in line with their clinical routine.  
Patient memory aids will be distributed to the patients. The patient can note in this memory aid all 
information important to recall when he/she is asked by his/her physician. The memory aid is to 
be used on a voluntary basis and will not be collected by the site. 
Table 5 (Section 9.4) outlines the data to be collected with associated timings. The data sources 
used in this study are clinical records, and data from telephone interviews.  
 
9.2.1. 
Participating Sites 
About 660 hospital- and office-based physicians [general practitioners, internal medicine 
physicians and other specialists] in 11 European countries [Austria, Belgium, France, Germany, 
Ireland, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom] are planned to 
participate in the study. For regional comparisons, the following regions are pre-specified: 
DACH 
 
Austria, Switzerland and Germany (around 250 sites)  
UK/IE 
 
United Kingdom and Ireland (around 75 sites) 
FR 
 
France (around 100 sites) 
BE/NL 
 
Belgium, The Netherlands (around 70 sites) 
ES/PT 
 
Iberia with Spain and Portugal (around 90 sites) 
IT 
 
Italy (around 75 sites). 
 
For site selection, a stepwise process will be performed to allow for representative regional 
distribution of sites, site specialities and health care settings of the acute VTE treatment with 
edoxaban. First, different databases are used to put a site list of potential sites together (Daiichi 
Sankyo internal database, CRO Investigator CTMS database, external databases as available).  
To take different site characteristics into consideration the sites will be asked to specify site details 
(e.g. size of site or location) in a site qualification questionnaire before being chosen for study 
participation. At least 5 times the targeted number of active sites are contacted. If a site fulfils the 
requirements to participate in the study, the corresponding CRO will inform the site. These 
contacted sites are free to accept or refuse to participate within the ETNA-VTE-Europe.  
The site must meet the following criteria in order to be selected for participation in this study: 
 To have access to patients with acute VTE who are expected to be treated with 
edoxaban during the 2 years recruitment period. 
 To be able to document the data in English language.  

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 To be able to access the EDC system, reliable internet connection [broadband] and 
computer. 
 To be able to conduct the study adequately, with enough time and staff to identify 
eligible patients, conduct the patient consent process, participate in required trainings, 
enter study data, and follow-up with study related activities. 
 To agree, to follow up the patients according to the clinical practice.  
 To ensure patient representativeness every site is ask to fill in a screening log to 
ensure consecutive enrolment of patients. The enrolment per site is initially capped 
with a maximum of 10 patients. Based on the development of the enrolment, the cap 
may be adjusted throughout the study.  
Sites who have not recruited any patient in the first 12 months after site initiation can be excluded 
from further participation. 
 
9.2.2. 
Eligibility Criteria 
Patients can be enrolled when they fulfil the following inclusion criteria: 
 Established acute initial or recurrent VTE  
 Patients treated with edoxaban according to Summary of Product Characteristics. 
Patients will only be included in the study after the treating physician has made the 
clinical decision to prescribe edoxaban ensuring that the prescribing behavior of the 
physician is not influenced. 
 Written informed consent for participation in the study 
 Not simultaneously participating in any interventional study  
 
As this is a non-interventional study, no additional selection criteria apply.  
 
A simultaneous participation in any other non-interventional study/registry is allowed. No other 
explicit exclusion criteria exist to avoid selection bias and to allow for documentation of routine 
clinical practice. 
Sites will be asked to complete a patient screening log of eligible patients for ETNA-VTE- Europe 
at their treatment centres. This log will document patients treated with edoxaban who have not 
been included into the study, in order to assess the representativeness of the study population. 
Minimal, non-identifiable information will be recorded for these patients, but no patient-
identifiable information should be recorded.  
 

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9.2.3. 
Patient Groups 
There are no formal patient groups planned. However, in case a patient permanently discontinues 
edoxaban treatment in the course of the observation period, he/she will be followed up in a separate 
group as scheduled at baseline or until the end of the 18 months observational period per patient 
is reached.  
For this group, safety reporting for drugs other than edoxaban will be covered outside the scope of 
this study through the local processes of spontaneous reporting by the treating physician(s). The 
eCRF will be customized to allow for documentation of other therapies. During the follow up 
period for both the edoxaban and discontinued groups, the data documentation schedule will be 
applied in the same manner. 
 
9.2.4. 
Schedule 
The total study period from FPI to LPO is 59 months. The individual start per country depends on 
market availability of edoxaban and will range approximately from Q4 2016 to Q1 2017. Thus, it 
is currently anticipated that the last patient will complete the ETNA-VTE-Europe in Q4 2020.  
The study started patient enrolment already in August 2015 in Germany, however, patient 
enrolment was set on hold until PRAC approval of the protocol is received and the positive 
opinions of the ECs in charge are received. 
As the observational plan for the ETNA-VTE-Europe has already been approved by the 
Swissmedic in its original version (V1.0, from 20 Feb 2015), and also the positive vote of the 
central Ethics Committee in Switzerland has been received, the Swiss sites are able to enrol 
patients. However, once PRAC approved the revised ETNA-VTE-Europe protocol, the Swiss 
regulatory bodies will be informed about the protocol changes and their approval will be sought 
as well. Once this is received, the revised protocol will also be implemented in Switzerland.  
Per country, the patient recruitment period consists of 24 months, followed by an 18 months follow 
up period per patient, summing up to 42 months per country.  
Documentation of patient data will be offered at 6 points in time (for reference see Figure 2):  
 Baseline (BL) at enrolment (beginning with the first heparin administration) 
 FU1 approximately 1 month after baseline  
 FU2 approximately 3 months after baseline 
 FU3 approximately 6 months after baseline 
 FU4 approximately 12 months after baseline 
 FU5 approximately 18 months after baseline 
 In addition, recurrence of symptomatic VTE and death will be captured 
retrospectively at time point of LPO per country  
 

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For variables to be documented at the different data collection time points refer to Section 9.3 and 
Section 9.4. Follow up data collection points will be planned and conducted according to the 
clinical practice on the discretion of the treating physician. Those patients who will not see 
routinely the treating physician again, might be followed up by phone using standardized telephone 
interview.  The patient is asked within the ICF, whether he/she is willing to get contacted by the 
treating physician for standardized telephone interviews and needs to agree to provide contact 
details as long this procedure is in line with the clinical practice  
If possible, the follow up data collection points of patients, who permanently discontinued 
edoxaban treatment, will be at the same intervals as for all patients (see Section 9.2.5).  
 
Figure 2: 
Study schedule 
 
 
9.2.5. 
Permanent Discontinuation of Edoxaban 
If a patient’s treatment on edoxaban is permanently discontinued or temporarily interrupted due to 
any reason at any time after the baseline visit, this information needs to be documented in the 
eCRF during the respective next follow up data collection point. 
 
9.2.6. 
Early Study Termination  
In case a patient terminates the study early, reason for early study termination (lost to follow-up, 
investigator’s decision, adverse events, withdrawal of consent etc.) will be recorded.  
The treating physician should at least get awareness of the patient’s vtial status at the time of the 
early termination of participation in the study.  

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Withdrawal of Consent from PASS Participation  
 
In accordance with the Declaration of Helsinki and other applicable regulations, a patient has the 
right to withdraw consent for participation in the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution. 
If a patient 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 anticoagulation therapy. The investigator will clearly document the reason 
(if given) for consent withdrawal in the medical record and will complete the associated electronic 
case report form (eCRF) section. 
 
9.3. 
Variables 
To allow for comparability with the outcomes of the PREFER in VTE registry as well as the 
Hokusai-VTE interventional study, the variables and approaches are defined as close as possible 
to the ones used in PREFER in VTE/Hokusai-VTE and as feasible in a non-interventional trial.  
 
9.3.1. 
Exposure Definition 
This is a non-interventional study of real-world use patterns of patients taking edoxaban. The 
protocol does therefore not recommend the use of any specific treatments. No study medication is 
provided to the sites or patients by the sponsor. 
As a long-term, non-interventional study to evaluate safety and clinical outcome in patients treated 
with edoxaban in the post-authorization setting, no restrictions on concomitant treatments are 
associated with the study. Relevant concomitant treatments will be recorded as described further 
in Section 9.4.1 Baseline/Enrolment (beginning with the first heparin administration) and 
Section 9.4.2 Follow-up in order to evaluate their potential influence on the outcomes of interest.  
Exposure to edoxaban will be based on the data obtained from the prescribing health care 
providers. Treatment with edoxaban will be characterized according to the VTE relevant 
concomitant medication used at that time. Persistence to therapy will be assessed by looking at the 
rate and reasons of permanent discontinuation of edoxaban and the duration of time on therapy. In 
addition, physicians will be asked how they estimate the compliance to edoxaban therapy. 
 
All time under observation for enrolled subjects will be classified in the following categories of 
exposure for use of edoxaban: 
 Current use: Beginning the day of medication start through date of last use 
 Recent use: Beginning after the last date of current use continuing for 3 days 
 Past use: Beginning after 3 days of the last date of current use and continuing through 
end of study follow-up 

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The recent use exposure period is recommended to define a brief period during which increased 
biologic effects may be expected to persist after edoxaban use is terminated and to set apart from 
other non-use. 
 
Furthermore, a sensitivity analysis will be performed based on a fourth exposure category: 
 Extended-recent use: Beginning after the last date of current use continuing for 30 
days 
 
Patients switching to another antithrombotic therapy or no therapy at all will be evaluated 
depending on the proportions documented. Details will be described in the SAP.  
 
9.3.2. 
Safety Measures 
The co-primary objective of this study is to collect and evaluate real-world safety data on bleeding 
events, drug related adverse events such as liver adverse events, and mortality (VTE-related, CV 
mortality, and all-cause mortality) in patients treated with edoxaban. 
 
Safety measures therefore include: 
 Major bleeding (for definition please see below) 
 Clinically relevant non-major bleedings (for definition please see below) 
 Minor bleeding  
 Adverse drug reactions (for definition please see Section 11.1) 
 
In addition, mortality (VTE-related, CV mortality, and all-cause mortality) will be assessed. 
 
Special focus will be given to safety in certain patient subgroups as renal or hepatic impaired 
patients. 
 
Definition for bleeding events: 
Major bleeding event: 
A clinically overt bleeding event (i.e. bleeding that is visualized by examination or radiologic 
imaging) that meets at least one of the following: 
a) Fatal bleeding 
b) Symptomatic bleeding in a critical area or organ such as: 
 Retroperitoneal 

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 Intracranial 
 Intraocular 
 Intraspinal 
 Intra-articular 
 Pericardial 
 Intramuscular with compartment syndrome 
c) A clinically overt bleeding event that causes a fall in haemoglobin level of 2.0 g/dL (> 1.24 
mMol/L) or more, adjusted for transfusions. Each unit of packed red blood cells or whole blood 
is counted as a 1.0 g/dL decrease in haemoglobin. In the case of surgical procedural related 
bleeding, the bleeding must be in excess of that normally associated with the 
surgery/procedure. In the absence of haemoglobin data, a fall of haematocrit of 6.0% or more, 
adjusted for transfusion, will satisfy the criteria for a major bleeding event. 
Major bleeding events will also be further subclassified as life-threatening or non-life threatening. 
A life-threatening major bleed is defined as a bleeding event that is either intracranial or is 
associated with haemodynamic compromise requiring intervention. 
 
Clinically relevant non-major bleeding events: 
A clinically overt bleeding event that requires medical attention that do not fulfil the criteria for 
major bleeding event. Examples of bleeding requiring medical attention include, but are not limited 
to, bleeding events that result in the following diagnostic or therapeutic measures: 
 Requires or prolongs hospitalization 
 Laboratory evaluation 
 Imaging studies 
 Endoscopy, colonoscopy, cystoscopy, or bronchoscopy 
 Nasal packing 
 Compression 
 Ultrasound guided closure of an aneurysm 
 Coil embolization 
 Inotropic support 
 Surgery 
 Interruption or stopping anticoagulation at the advice of a physician 
 Changing concomitant therapies (eg. reducing the dose of or discontinuing aspirin) at 
the advice of a physician 
 

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Note: an outpatient data collection point without any of the above or similar diagnostic/therapeutic 
measures does not satisfy the criteria for ‘requiring medical attention’. 
 
Other overt bleeding events that do not fulfil the criteria of a major bleeding event or a clinically 
relevant non-major bleeding event (eg. epistaxis that does not require medical attention) will be 
classified as a minor bleeding event. 
 
NOTE: All other events (eg. decline in haemoglobin with no overt bleeding event) will be 
classified as ‘no bleeding event’. 
 
9.3.3. 
Effectiveness Measures 
Effectiveness will be assessed by the following outcomes: 
 Symptomatic recurrence rate of VTE for patients on edoxaban and  
 Symptomatic recurrence rate of VTE for patients who permanently discontinued 
edoxaban 
 Strokes (ischaemic and haemorrhagic)  
 SEE (systemic embolic events) 
 Hospitalisations related to CV condition (including VTE related hospitalisation) 
 Post thrombotic syndrome  
 
9.4. 
Data Sources 
Scheduled documentation time-points for the study are presented in the Data Collection Flow 
Chart provided below (Table 5). All data elements will be collected from information routinely 
recorded in the patient files/medical records or during telephone follow-up interviews. No data 
collection points or examinations, laboratory tests or procedures are mandated as part of this non-
interventional study. 
 
9.4.1. 
Baseline/Enrolment 
The following data will be collected at baseline for all enrolled patients: 
 Demographics i.e. 
o Age 
o Gender 
 Vital Signs i.e. 

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o Blood pressure 
o Heart rate 
o Height 
o Weight 
 Medical History (past and current status) i.e. 
o Relevant comorbidities present at baseline (e.g. diabetes, COPD, dyslipidemia) 
 VTE-History, Diagnosis and Interventions (past and current status) i.e. 
o Type of VTE (DVT or/and PE, first or recurrent), date of first diagnosis, 
symptoms at first diagnosis and current, etc. 
o Type of interventions, date and number of interventions 
 VTE-related clinical events (past and current status) i.e. 
o Stroke (ischemic and hemorrhagic), bleeding events, systemic embolism, non-
valvular atrial fibrillation, malignancies, others 
 Hospitalisations related to CV condition (including VTE related hospitalisation) 
 VTE-related treatment (past and current) 
 Heparin treatment (dose, duration) 
 Edoxaban treatment (past and current) 
 Other VTE-relevant patient information e.g. 
o Bleeding disposition 
o Thrombocytopenia 
o Alcohol consumption 
o Smoking status 
o Frailty 
 Hospitalisations related to CV condition (including VTE related hospitalisation) 
o Start/Stop date 
o Emergency Room 
o Intense Care Unit 
o Clinical Event 
 
The necessary data to calculate BMI and risk scores (e.g. HASBLED) will be documented by the 
site. BMI and risk scores will be calculated automatically by the EDC system. 
 
 

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Table 5: 
Data Collection Flow Chart 
CRF-Forms 
BL 
FU1 
FU2 
FU3 
FU4 
FU5 
(FU 6)** 
Time point [months] 
0 
1* 
3* 
6* 
12* 
18* 
LPO ** 
Date  
x 
x 
x 
x 
x 
x 
 
Eligibility  
x 
  
  
  
  
 
 
Demographics  
x 
  
  
  
  
 
 
Physical examination 
  
  
  
  
  
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
 
VTE and other related diseases 
  
  
  
  
  
 
 
VTE history & current status: Diagnosis and 
interventions  
x 
 
 
 
 
 
 
VTE recurrence: Diagnosis and interventions 
 
x 
x 
x 
x 
x 
 
Medical History  
x 
 
 
 
 
 
 
Concomitant Medication  
x 
x 
x 
x 
x 
x 
 
Lab parameters (as available) 
x 
x 
x 
x 
x 
x 
 
Other VTE-related clinical events  
x 
x 
x 
x 
x 
x 
 
Other disease history 
x 
 
 
 
 
 
 
Assessment of post-thrombotic syndrome (as 
available) 
 
 
x 
 
x 
x 
 
Hospitalizations 
  
x 
x 
x 
x 
x 
 
VTE related therapy  
  
  
  
  
  
 
 
VTE-related therapy  
x 
  
  
  
  
 
 
Edoxaban therapy (history/current/since last data 
collection point) 
x 
x 
x 
x 
x 
x 
 
 
 
  
  
  
  
  
 
 
VTE therapy compliance (physician judgment 
only) (optional) 
x 
x 
x 
x 
x 
x 
 
  
  
  
 
 
ADR reporting for edoxaban 
Continuously 
- 
Permanent discontinuation of edoxaban 
(reasons, subsequent therapy) 
if applicable 
- 
Final assessment 
at premature study termination or final FU data 
collection point 
x** 
*based on the regular clinical care this data collection point may be conducted in person or by phone (depending on 
the availability of the patient and according to the clinical routine practice)  
** at time point of last patient out per country; retrospective data collection on recurrent VTE only (YES/NO) since 
FU5 

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9.4.2. 
Follow-up 
The following data are planned to be collected at the FU data collection points:   
 Date of documentation  
 Current vital signs and weight 
Additionally any change in the current status needs to be recorded regarding: 
 VTE recurrence  
 VTE symptoms and diagnostics 
Any change since the last data collection point needs to be recorded for: 
 Edoxaban exposure  
 Diagnosis 
 Medication changes 
 Other anticoagulant treatment 
 Interventions 
 Clinical Events 
 Hospitalisations related to CV condition (including VTE related hospitalisation) 
 Other VTE relevant patient information 
 
To facilitate data entry in the eCRF, the following forms (so called common folders) can be 
accessed at any time and allow an ongoing documentation: 
 VTE recurrence form 
 Edoxaban treatment form 
 VTE-related treatment form (heparin/fondaparinux, systemic thrombolysis, NOACs, 
VKA, antiplatelets, other relevant treatments) 
 VTE relevant clinical events (stroke (ischemic and hemorrhagic),  bleeding events, 
SEE, non-valvular atrial fibrillation, malignancies, other VTE relevant clinical 
events) 
 Hospitalisations related to CV condition (including VTE related hospitalisation) 
 Adverse drug reactions 
 
Reporting of patients’ compliance by investigator judgement to edoxaban therapy is asked to be 
recorded at each data collection point (optional)  

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Data from routine patient data collection points or telephone interviews at the respective site 
should be documented directly in the Medical Records and entered shortly thereafter into the 
eCRF. 
 
9.4.3. 
Adverse Drug Reaction Reporting 
In case a patient experiences an adverse event that the investigator judges to be related to edoxaban, 
this ADR needs to be documented immediately and data collection point independent in the 
respective eCRF section (refer to Section 11).  
The ADR documentation, processing and reporting follows the Guideline on Good 
Pharmacovigilance Practices (GVP) Module VI (Management and reporting of adverse reactions 
to medicinal products). 
 
9.4.4. 
Edoxaban Treatment Discontinuation  
In case a patient permanently discontinues treatment with edoxaban the treatment discontinuation 
needs to be documented as part of the subsequent follow up data collection point. 
 
The following data should be captured: 
 Date of treatment discontinuation  
 Details and reason for discontinuation (in case of an event or hospitalization this 
needs to be captured as well) 
 Future anticoagulation therapy intended (to be documented in the form VTE-related 
treatment or edoxaban treatment respectively). 
It is recommended that the site documents this information as soon as it becomes aware of the 
permanent discontinuation of edoxaban. 
 
9.4.5. 
Final Assessment  
At the end of the follow up period (i.e. 18 months after enrolment) or at early study termination 
the final assessment needs to be documented.  
The final assessment includes: 
 Date of final assessment 
 Reason for final assessment (e.g. end of observational period reached, withdrawal of 
consent, death, transfer to another institution, lost to follow up) 
 Intended further treatment for VTE 
 

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9.5. 
Study Size  
Sample size justification with respect to primary objective: 
The overall recurrence rate of symptomatic VTE during the 18 months observation period is 
assumed to be 8.0 % (0.08). The assumed rate refers to all patients regardless from the fact whether 
they stopped treatment with edoxaban during the 18 months or not. Assuming furthermore a 
relative precision of 15% (i.e. an absolute precision of 1.2% resp. 0.012), for a two-sided 95%-
confidence interval at least 1,964 patients are needed. Given a drop-out-rate of 25%, approx. 2,700 
patients should be included into the study.  
 
Sample size considerations with respect to co-primary objective: 
For the co-primary objective, i.e. to collect more real-world safety data the intention is to use a 
data pool as large as possible. Therefore, the safety data of this PASS (ETNA-VTE-Europe, DSE-
EDO-05-14-EU) will be combined with the safety data of a parallel edoxaban PASS (ETNA-AF-
Europe, DSE-EDO-04-14-EU), which allows the total dataset to be in line with the presentation 
of the safety profile in the European SmPC. ETNA-AF-Europe is conducted in non valvular atrial 
fibrillation (NVAF) patients and is going to recruit 13,100 patients. In both studies 15,800 patients 
shall be recruited. Assuming a common drop-out rate of 20% within the first 18 months, 12,640 
patients should be evaluable for the estimation of the 95% confidence intervals of the incidence 
rates of interest (i.e. major bleeding and mortality) after 18 months of follow-up. For uncommon 
adverse drug reactions (i.e. incidence rates between 0.1% and 1%), the 95% CIs will be estimated 
taking the actual number of patients into account. For the assumed number of 12,640 patients from 
the combined safety data bases, the 95% CI will have a precision ranging from ±0.06% for an 
incidence rate of 0.1% to ±0.17% for an incidence rate of 1%.The power will be sufficient to 
capture uncommon adverse drug reactions with low incidence rates. 
 
9.6. 
Data Management (DM) 
The Medidata Rave EDC system will be used for data capture. Data will be collected in 
standardised English eCRFs.  
A data management plan will be created in the study start phase and will describe all functions, 
processes, and specifications for data collection, cleaning and validation.  The eCRFs will include 
automated plausibility checks (e.g. range checks, conditional checks, etc.) at data entry to obtain 
immediate feedback if data are missing, out of range, illogical or potentially erroneous and allow 
for correction or confirmation by the site. Concurrent manual data review will be performed based 
on parameters defined in the data management plan. If necessary, queries will be manually 
generated within the EDC system and followed up for resolution.  
Critical fields will be defined that need to be filled in by the site prior to signing the eCRF.  
Data from the project specific Rave database will be exported into SAS and converted into CDISC 
SDTM standardized datasets for further validation and analysis.  
For (S)ADRs a reconciliation will be performed as described in the (S)ADR Reconciliation Plan. 

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9.6.1. 
Data Entry/Electronic Data Capture 
Data will be collected and entered directly into the Medidata Rave EDC system. Each participating 
site will have access to the data of its own enrolled patients. All sites will be fully trained on using 
the on line data capture system, including eCRF completion guidelines and other help files. Sites 
will be responsible for entering patient data into the secure internet-based EDC database via the 
eCRF. Investigators and other site personnel will access their account with a unique username and 
password. All eCRFs should be completed by designated and trained personnel, as appropriate. 
Each eCRF has to be reviewed and electronically signed and dated by the investigator. All changes 
or corrections to eCRFs are documented in the audit trail and an adequate explanation is required.  
 
9.6.2. 
Source Documents 
In most cases, the source documents are contained in the patient’s medical record and data 
collected on the eCRFs must be traceable to these source documents in the patient’s medical 
records. In some cases, the eCRF, or part of the eCRF, may also serve as source documents. In 
these cases, a document should be available at the investigator’s site clearly identifying those data 
that will be recorded directly in the eCRF, and for which the eCRF will stand as the source 
document. All original source documentation is expected to be stored at the site for the longest 
possible time required by local applicable regulations. The site will be instructed to notify the 
sponsor before any destruction of medical records of study participants. 
 
9.6.3. 
File Retention and Archiving 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating patients, all original signed 
informed consent forms, and source documents. The records should be retained by the investigator 
according to local regulations, or as specified in the study contract, whichever is longer. 
Each site will receive a study site file at study initiation which contains all documents necessary 
for the conduct of the study that is updated throughout the study. This file must be available for 
review in the event the site is selected for monitoring, audits, or inspections and must be safely 
archived for at least 10 years or according to local legislation respectively after completing the 
participation in the study. Documents to be archived include the patient identification list, 
screening log, copy of eCRF burned on a CD, and the signed informed consent form (ICF) and the 
site contract.  
 
9.7. 
Data Analysis 
9.7.1. 
Overview on planned analyses 
The following two analyses are planned:  

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1. Final analysis on the data of the ETNA-VTE-Europe study (including comparison of the 
results with the respective results of the PREFER in VTE (disease registry) as well as with 
the results of the Hokusai-VTE study (clinical trial)) 
 
2. Combined safety analysis of ETNA-AF-Europe and ETNA-VTE-Europe based on the 18-
months safety data of both studies, which will refer to the co-primary endpoint of this study 
(will be reported separately).  
 
For these analyses two separate Statistical Analysis Plans will be written. 
 
Three data snapshots of the ETNA-VTE-Europe are planned and will be analysed before the final 
analysis will take place after data base lock: 
1. Snapshot: 
 
Q1 2018  
2. Snapshot: 
 
Q1 2019 
3. Snapshot: 
 
Q1 2020 
Combined Analysis   
Approx. Q1 2021 
 
All analyses will contain a summary of all data plus a summary of data per country/region.  
 
The writing of the SAP for the ETNA-VTE-Europe will start right after the finalisation of the 
observational plan and a version 1.0 of the SAP will be available before the (re-)start of the study 
after final PRAC approval. If the SAP needs to be revised for a snapshot or the final analysis, the 
adaptation will always be finalised and signed before the extraction of data for the respective 
snapshot or the final data base lock, respectively. 
 
The time point of the combined safety analysis is triggered by the 18-months data collection point 
of the last patient from the ETNA-VTE-Europe and will be based on the data base lock for the 
ETNA-VTE-Europe (which will come before the 2 years data collection point of the ETNA-AF-
Europe, presumably Q2 2021. All events during edoxaban treatment with an onset date of ≤ 18 
months relative to the baseline data collection point will be included in this 1.5-year safety 
analysis.  
 
The final European analysis and report will be performed after the planned end of the data 
collection (Q4 2020) and data lock and will cover all data from all countries to allow for 
comparability.  
 

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The report will include - but is not limited to - descriptive statistics of all documented parameters 
overall, per region and per country. Details will be given in the SAP and in the statistical section 
of the report. Interpretation of all results will be purely descriptive/explorative.  
 
9.7.2. 
Overview on the statistical methodology 
All computations and generation of tables, listings and data for figures will be performed using 
SAS® version 9.3 or higher (SAS Institute, Cary, NC, USA).  
The statistical analyses will be performed in a purely explorative descriptive way based on the 
non-interventional character of this study. While the principal conduct of the statistical analysis 
will follow DSE SOP R-440 (which is understood as an umbrella SOP), concrete statistical 
procedures will be performed in accordance to the more specific SOPs of Quintiles.  
All ADR verbatim terms will be recorded and coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  
All statistical methodology will be described in detail in the Statistical Analysis Plan (SAP) for 
which a version 1.0 of the SAP will be available before the start of the study after final PRAC 
approval.  
All variables collected in the CRFs as well as all derived parameters will be used in the statistical 
analysis. Any derivation of parameters, corrections of inconsistencies and imputations of values 
will be described in the respective SAP section.  
Each table will be presented in general for VTE as well as by the diagnoses PE (i.e. PE ± DVT) 
and DVT (i.e. DVT only). 
Categorical variables will be summarized by the number and percentage (%) of patients in each 
category. Continuous variables will be summarized using number of non-missing observations, 
number of missing observations, mean, SD, median, first quartile and third quartile, minimum and 
maximum values. The 95% CIs will also be provided for selected variables. 
In addition, adequate graphs (e.g. bar charts, box-whisker plots) may be presented.  
Kaplan-Meier plots will be generated where applicable to characterize the risk over time for each 
outcome.  
Time-to-event variables will be analysed via a Cox proportional hazard regression model 
presenting hazard ratios and corresponding 95% confidence intervals and p-values for 
comparisons of the pre-defined subgroups. All Cox models will include diagnosis as an additional 
covariate. 
 
 
 
 
 

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9.7.3. 
Analysis of primary endpoint 
The primary endpoint refers to the overall study period of 18 months. 
 
Analysis of primary endpoint within the data of ETNA-VTE study 
For the primary endpoint, the overall symptomatic VTE recurrence rate during an overall 
observational period of 18 months, absolute and relative frequencies (including the 95% 
confidence interval) will be presented. 
Furthermore, for the primary endpoint, the following subgroups will be descriptively compared: 
 renal impairment (yes, no) 
 hepatic impairment (yes, no) 
 diagnosis (PE with/without DVT, DVT only) 
 age (< 75 years, ≥ 75 years) 
 gender (male, female) 
 initial edoxaban dose (30mg, 60mg) at study start 
 active cancer at randomization (yes, no) 
 
Further comparisons of the above subgroups will be done via Cox proportional hazard regression 
models presenting hazard ratios and corresponding 95% confidence intervals. Again, the 
interpretation of the results will be purely descriptive/explorative. All Cox models will include 
diagnosis as an additional covariate. Based on the results of the HOKUSAI-VTE and the PREFER 
in VTE, there are no further confounders that need to be considered upfront. Nevertheless, if 
relevant differences in Baseline characteristics are detected, these variables will be added to the 
model as additional covariates. 
 
In addition, Kaplan-Meier estimates will be calculated for the first re-occurrence of VTE. 
 
Setting into perspective with results from the other studies (PREFER in VTE and the Hokusai-
VTE) 
The obtained result for the primary endpoint are compared with results from other studies, namely 
the PREFER in VTE and the Hokusai-VTE.  Both of these studies had only an observation period 
of one year. Therefore, also for the ETNA-VTE-Europe the observed recurrence rate for VTE after 
one year is calculated. It will be set into perspective with the recurrence rate after 1 year from the 
Hokusai-VTE and the PREFER in VTE registry for: 
o patients treated with NOACs (PREFER in VTE registry)  
o patients treated with a VKA (PREFER in VTE registry)  
o patients treated with edoxaban in a clinical setting (Hokusai-VTE) 

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o patients treated with warfarin in a clinical setting (Hokusai-VTE)  
 
The comparisons will be purely descriptive/explorative, i.e. the obtained rates from the ETNA-
VTE-Europe will just be contrasted with the respective rates obtained in the PREFER in VTE 
registry and the Hokusai-VTE, respectively. There will be no joint model that compares the 
different treatments directly.  
 
Analysis of the co-primary endpoint (based on combined 18-month safety data) 
One focus of the analysis of the combined 18-month-safety data will be the estimation of the 
incidences of ADRs and especially the detection of rare ADRs. Therefore, the analysis will include 
at least but is not limited to the presentation of: 
 absolute and relative frequencies of all ADRs, listed separately by primary System 
Organ Class (pSOC in internationally agreed order) and Preferred Term (with order 
of PT in descending order of incidence). 95%-CIs for the proportion will be presented 
in addition. 
 absolute and relative frequencies of all ADRs (listed as described above) for all 
subgroups of patients that are specified for the ETNA-AF-Europe (please see 
Section 9.7.3 of the observational plan of the ETNA-AF-Europe) as well as for the 
ETNA-VTE-Europe (please see above)  
 
Furthermore, it will be looked at 
 major bleedings (for definition, see 9.3.2) 
 clinically relevant non-major bleedings (for definition, see 9.3.2) 
 minor bleeding  
 hospitalisations related to CV condition including VTE related hospitalisations  
 mortality (VTE-related, CV-related and all cause) 
 
Data will be summarized descriptively and presented for all exposure categories (see 9.3.1 for 
details). 
 
These analyses will be repeated for all the subgroups of patients that are specified for the ETNA-
AF-Europe (please see Section 9.7.3 of the observational plan of the ETNA-AF-Europe) as well 
as for the ETNA-VTE-Europe (please see above). 
 
All the above outlined analyses of the combined 18 month safety data will be repeated for the data 
of the ETNA-VTE-Europe only, if they are not already covered by the secondary objectives. 

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9.7.4. 
Analysis of secondary endpoints 
Analysis of secondary endpoints within the data of ETNA-VTE study 
 
While the primary endpoint only refers to all patients during the whole observation period and 
does not consider whether patients are still treated with edoxaban or not, within the secondary 
endpoints it is additionally looked at the  
 recurrence rate of VTE in the single exposure categories (i.e. current use, recent use 
and past use, and - as a sensitivity analysis – extended recent use). 
 
The analyses will follow the above outlined analysis of the primary endpoint. Absolute and relative 
frequencies (including the 95% confidence interval) will be presented.  
Further secondary objectives of the study that mainly refer to the effectiveness of Edoxaban are: 
 Stroke (ischaemic and haemorrhagic) 
 SEE 
 Hospitalisations related to CV condition including VTE related hospitalisation  
 Post-thrombotic syndrome (PTS) 
 
Other secondary objectives not related to the effectiveness do cover 
 Extent of exposure and compliance by investigator judgment to edoxaban therapy, 
rate and reasons of permanent discontinuation of edoxaban 
 Malignancy 
 
For all secondary endpoints, summary statistics, frequencies and rates (including the 95% 
confidence interval) will be presented overall and within the different exposure categories (see 
9.3.1 for details). Kaplan-Meier estimates will be calculated for the first occurrence of re-
occurrence of stroke (ischaemic and haemorrhagic), SEE, and malignancy. Again, for the Kaplan-
Meier estimates only the overall observational period will be looked at.  
 
In analogy to the primary endpoint, comparisons of patients will be performed for the following 
subgroups  
 renal impairment (yes, no) 
 hepatic impairment (yes, no) 
 diagnosis (PE with/without DVT, DVT only) 
 age (< 75 years, ≥ 75 years) 
 gender (male, female) 

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 initial dose (low, high) 
 active cancer at randomization (yes, no) 
 
These comparisons will be performed purely descriptively presenting summary statistics, 
frequencies or rates. For all secondary endpoints (except for hospitalizations related to CV 
conditions, permanent discontinuations from edoxaban therapy, reasons for permanent 
discontinuation, duration on therapy as well as compliance rating and post thrombotic symptom) 
results of the Cox proportional hazard regression models are presented as well (hazard ratios and 
corresponding 95% confidence intervals). All Cox models will include diagnosis as an additional 
covariate. Based on the results of the PREFER in VTE and the HOKUSAI-VTE, there are no 
further confounders are considered upfront. Nevertheless, if relevant differences in Baseline 
characteristics are detected, these variables will be added to the model as additional covariates. 
 
Comparison for hospitalizations related to CV conditions, permanent discontinuations from 
edoxaban therapy, reasons for permanent discontinuation, duration on therapy as well as 
compliance rating and post thrombotic symptom will only be performed by means of absolute 
numbers and percentages or by means of standard statistics.  
 
Setting the results for the secondary endpoints into perspective with results from the other studies 
(Hokusai-VTE and the PREFER in VTE) 
Results of the ETNA-VTE-Europe will be put in perspective to the results from the Hokusai-VTE 
and the PREFER in VTE registry for: 
 patients treated with NOACs (PREFER in VTE registry)  
 patients treated with a VKA (PREFER in VTE registry)  
 patients treated with edoxaban in a clinical setting (Hokusai-VTE) 
 patients treated with warfarin in a clinical setting (Hokusai-VTE)  
 
As both, the Hokusai-VTE as well as the PREFER in VTE registry, had an observation period of 
one year, for all secondary endpoints of the ETNA-VTE study the corresponding summary 
statistics, frequencies and rates, respectively, after one year will be calculated. The 95% confidence 
intervals will also be provided. These results will be contrasted with the corresponding results from 
the Hokusai-VTE and the PREFER in VTE registry.  
 
It is important to understand that these comparisons will be purely descriptive/explorative and that 
there will be no joint model that compares the different treatments directly. Furthermore, although 
every effort was made to align the endpoint definitions of the ETNA-VTE as much as possible to 
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endpoints are highly harmonised but not necessarily identical. The SAP will explicitly outline this 
for each endpoint. 
 
The results will be presented overall by countries and regions as well as for the above-specified 
subgroups, namely 
 renal impairment (yes, no) 
 hepatic impairment (yes, no) 
 diagnosis (PE with/without DVT, DVT only) 
 age (< 75 years, ≥ 75 years) 
 gender (male, female) 
 initial dose (low, high) 
 active cancer at randomization (yes, no). 
 
Further data like patient characteristics or laboratory data will be summarized as appropriate, i.e. 
by means of absolute numbers and percentages or by means of standard statistics. 
Additional exploratory analyses may be performed and will be outlined in the SAP prior to 
analysis. 
 
9.8. 
Quality Control 
This study will be conducted according to the rules of ‘Good Pharmacoepidemiology Practice’ 
(GPP) and the ‘Guideline on Good Pharmacovigilance Practices (GVP) – Module VIII (Rev 1)’ 
EMA/813938/2011 Rev 1. Related quality control mechanisms (e.g. data plausibility checks, 
monitoring of data) will be performed accordingly. 
The physician will comply with the confidentiality policy as described in the site contract. The 
physician will comply with the observational plan and the requirements described in the contract. 
The physician is ultimately responsible for the conduct of all aspects of the PASS at the study site 
and verifies by signature the integrity of all data transmitted to the sponsor.  
All monitoring details will be described in a separate Clinical Operations Plan (COP). 
On-site monitoring will be performed in approx. 30% randomly selected sites. During on-site 
monitoring the monitor will verify 100% of informed consent documentation and perform source 
data verification against the patient’s medical records in randomly selected patients (approx. 3 per 
site).  
Data quality checks will be performed on an ongoing regular basis. Queries will be raised by the 
responsible CRO and shall be answered by the site in due course. The purpose is to ensure that the 
rights of the patients are protected, that the reported data is accurate and complete, and that the 

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conduct of the study is in compliance with the Observational Plan and applicable regulatory 
requirements. 
Particular attention will be paid during monitoring activities to the completeness and correctness 
of safety data. 
 
9.9. 
Limitations of the Research Methods 
As this study aims at collecting real-world evidence, some limitations common to non-
interventional studies apply. In addition, the following aspects need to be considered: 
 Although sites will be selected to guarantee representativeness for the respective 
country or region as much as possible, sites also need to have sufficient capabilities, 
interest and capacities to participate in the PASS and they need to be able to follow 
up a patient for 18 months at the site. This may influence the sites’ representativeness 
in some smaller regions. 
 Eligible patients not giving their informed consent to participate in the PASS cannot 
be enrolled. Therefore this may impact the consecutive enrolment at a site. To be able 
to assess the consecutiveness of enrolment, eligible patients will be listed in the 
patient screening log. Patients participating in competing interventional trials are not 
eligible and will not be entered in the screening list. 
 To allow for demonstrating patients included into the study are representative of 
patients prescribed edoxaban, a screening log will have to be completed by the sites, 
where all VTE patients with an acure VTE event or a VTE recurrence treated with 
edoxaban at the site need to be listed as well as the reason not to participate, age and 
gender. 
 At the documentation time point all relevant changes/events since the last 
documentation time point need to be entered. Due to the longer time between two 
data collection points an underreporting of data might occur that are not considered 
essential or that are difficult to remember. The patient memory aid and the patients’ 
medical records at the site shall support the precise documentation of the time 
between two data documentation time points. The utility of both records is however 
influenced by the precision and accuracy with which the memory aid and the medical 
records have been completed in the meantime. It is expected that possible 
underreporting will not appear in case of severe events and hospitalizations and that 
this data is considered to be representative for the whole study population.  
 In addition to the above mentioned underreporting of events, the time between two 
documentation points might cause a wrong documentation of treatment changes. This 
could lead to a misclassification with respect to the exposure. However, this risk is 
considered to be low as relevant treatment changes (i.e. those that are VTE-related) 
are usually documented in the medical records and can furthermore be entered into 
the eCRF at any time (log-file approach). In addition, the patient memory aid again 
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 In addition to confirm the robustness of the safety data from the ETNA-VTE study, 
the reported events from the study will be compared with the spontaneously reported 
events in the global safety database and external Electronic Medical Records data will 
be used to put the reported events into perspective to available local medical records 
collecting relevant outcomes from daily clinical practice.  
The Electronic Medical Records data will be evaluated for the information on the 
study’s primary objective which is symptomatic VTE recurrence rate and on the co-
primary objective of real-world safety data on bleeding events, drug related adverse 
events such as liver adverse events, and mortality in patients treated with edoxaban. 
Data will be summarized descriptively. If possible, Electronic Medical Records data 
will also be descriptively compared for certain subgroups, such as renal impairment, 
hepatic impairment, age, gender, edoxaban dose, and chronic concomitant antiplatelet 
use. 
Details of this descriptive comparison will be included in the SAP. 
Electronic Medical Records data is provided by PHARMO Database Network in the 
Netherlands. The PHARMO Institute can provide Electronic Medical Records data 
from the Netherlands and, through collaborations, other European countries where the 
use of edoxaban and relevant outcomes are captured in Electronic Medical Records 
from daily clinical practice. The data collected in the PHARMO Database Network is 
retrieved from electronic records at the source (i.e. the respective healthcare 
providers) and linked within the Network by a Trusted Third Party between the data 
source and the PHARMO Institute. Relevant data sources for this study include 
general practitioner, pharmacy, hospitalisation and laboratory databases. The 
PHARMO Institute works with several other databases in Europe which also include 
general practitioner (-based) databases, national registers, claims databases and 
pharmacy (-based) databases. The main event of interest is bleeding. This can be 
identified in hospital and/or primary records depending on the severity of the event. 
Other events of interest are rash, liver and renal abnormalities and nausea. Those can 
also be identified in hospital and/or primary records as well as in laboratory records, 
again depending on the severity of the event. Edoxaban users can be followed over 
time to monitor the occurrence of events of interest. These rates can be used to 
provide context for the rates found in the PASS. 
 For rating compliance, there might be differences due to different type of sites, 
namely hospital and office based sites. The respective tables will be stratified by type 
of site to detect these discrepancies (if any) and to allow for a careful and appropriate 
interpretation of the results. 
 Also differences between the countries/regions might occur, especially when rating 
compliance. Therefore, especially for the compliance the analysis by country/region 
will careful looked at. In case that there will be mentionable differences the 
interpretation has to be very careful and should consider regional differences. 
 As the study is non-interventional, only data from the clinical routine treatment can 
be obtained. Therefore some information may be missing or unavailable. This needs 
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No explicit non-eligibility criteria are defined to avoid selection of patients and thus violation of 
the 'real-life' principle. 
 
9.10. 
Other aspects 
Not applicable 
 

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10. 
PROTECTION OF HUMAN SUBJECTS 
10.1. 
Review by Ethics Committees/Competent Authorities 
Notification to or approval by institutional ethics committees (IECs) and competent authorities 
(CAs) or other organizations will be performed as required by national regulations in the 
participating countries before commencement of enrolment at a study centre. 
 
10.2. 
Insurance and Liability 
All treatments of patients included in this PASS are local standard of care and occur as part of the 
routine clinical practice. The study is non-interventional and does not foresee any change of 
treatment nor additional examinations apart from the standard of care. Claims of the patient upon 
his physician resulting from an inappropriate use of the edoxaban will not be covered by Daiichi 
Sankyo. Insurance coverage will only be provided with regards to the product liability. A specific 
patient insurance for PASS is not necessary (if not in contradiction with specific legal requirements 
in the country of conduct). 
 
10.3. 
Patient Information, Informed Consent  
Written Informed Consent (ICF) will be obtained from all patients before or on baseline data 
collection point and not thereafter.  
It is the responsibility of the investigator to inform the patient about his/her disease, possibilities 
for diagnostic and therapeutic measures, independent of a possible participation in any survey and 
therefore this information will not be part of the ICF.  
The written ICF will be provided to the sites in the local language(s) of the planned patient 
population. The ICF and any revision(s) should be approved by the Independent Ethics Committee 
(IEC) prior to being provided to potential patients. 
The patient's written informed consent will be documented in the patient's medical records of the 
investigator. Two ICF forms should be signed and personally dated both by the patient and by the 
investigator who conducted the informed consent discussion. One original signed ICF should be 
retained at the study centre (preferably in the patient's medical records). The second original of the 
signed consent form should be provided to the patient. The date informed consent was given will 
also be recorded in the Case Report Forms (eCRF).  
In addition, the patient has to agree with his/her signature to provide his/her contact details 
(address, phone number, email) to a separate data base in case the investigator contacts the patient 
for follow up. The patients must declare with a signature to agree to the follow-up by calls or email.  
 
10.4. 
Data Protection 
The patients' privacy will be kept according to the requirements of Directive 95/46 EC and national 
legislation for data protection. Data will be collected in a pseudonymous way. An identification 

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number assigned to each patient will be used in lieu of the patient’s name to protect the patient’s 
identity when reporting adverse drug reactions and/or other study-related data.  
All patient contact information required for follow-up calls will be kept strictly confidential and 
will only be accessible by the site. This personalized data will be stored separately from the project 
specific database on a server located in the EU and the data will be destroyed after database lock. 
Only authorised personnel at the site has access to the identification list or original source 
documents (medical records). Representatives of the sponsor, the contract research organisation 
(CRO), and authorities are allowed access in case of audit or inspection or for monitoring purposes. 
The patient will agree to this by signing a respective statement on the ICF.  
The database will be maintained under the global Daiichi Sankyo domain by the service provider 
with all safety instalments for a physically and logically secure computer system. The system is 
fully validated and in line with industry and regulatory standards. The system also meets the 
standards of the International Council on Harmonisation of Technical Requirements for 
Pharmaceutical for Human Use (ICH) guideline E6 R1 regarding electronic study data handling 
and is available for audit upon request. Patient confidentiality will be strictly maintained. 
 
10.5. 
Numbering and Identification of Patients 
A unique identification number (patient ID) will be assigned to each patient when reporting data 
in the eCRF or on the paper patient questionnaires. 
At each study centre a patient identification list will be kept linking the identification number to 
the patient’s identity.  
 
10.6. 
Assessments  
The investigators will be instructed about the correct documentation of the required variables for 
each patient in the eCRF. These data are available as part of the routine treatment. All examinations 
performed depend on the discretion and clinical routine of the physician. No diagnostic or 
monitoring procedures are applied to the patients in the study others than those performed as 
standard of care. 
 
 

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11. 
MANAGEMENT AND REPORTING OF ADVERSE DRUG 
REACTIONS  
All adverse drug reactions (ADRs) that are judged by the investigator as related to edoxaban need 
to be documented in the eCRF and will be reported according to the national requirements and 
local laws. The documentation and reporting follows the Guideline on Good Pharmacovigilance 
Practices (GVP Module IV). All ADRs have to be entered in the respective section of the eCRF 
as soon as the physician becomes aware of it. 
 
11.1. 
Definitions  
Adverse Drug Reaction (ADR) 
A response to a medicinal product which is noxious and unintended and which occurs at doses 
normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, 
correction or modification of physiological function. 
Response in this context means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility. 
Adverse reaction also includes adverse clinical consequences associated with use of the product 
outside the terms of the Summary of Product Characteristics or other conditions laid down for the 
marketing and use of the product (including prescribed doses higher than those recommended, 
overdoses or abuse). 
Serious Adverse Drug Reaction (SADR) 
Serious adverse reaction means an adverse reaction which  
 Results in death,  
 Is life-threatening,  
 Requires inpatient hospitalisation or prolongation of existing hospitalisation,  
 Results in persistent or significant disability or incapacity, or  
 Is a congenital anomaly/birth defect. 
Life threatening in this context refers to a reaction in which the patient was at risk of death at the 
time of the reaction; it does not refer to a reaction that hypothetically might have caused death if 
more severe. 
Medical and scientific judgement should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalisation but might jeopardise the patient or might require 
intervention to prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for severe allergic reactions, blood 
abnormalities or convulsions that do not result in hospitalisation or development of dependency or 
abuse. 
 

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11.2. 
Reporting of Suspected ADRs by the Investigator 
All occurring edoxaban related adverse reactions need to be documented in the eCRF by the site. 
The pharmacovigilance department of the sponsor (Daiichi Sankyo Europe GmbH, Clinical Safety 
& Pharmacovigilance Department, Zielstattstrasse 48,-81379 Munich, Germany) and the local 
safety officers (LSO) at the Daiichi Sankyo affiliate will receive an automated notification email 
if the ADR is entered into the eCRF. All ADR details will be obtained from the eCRF and will be 
processed further in line with the requirements for spontaneous reporting and in accordance with 
the Guideline on Good Pharmacovigilance Practices (GVP). 
 

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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
For publishing the study results a separate publication plan will be set up by the scientific Steering 
Committee. The final study report will be made publicly available within 6 months after LPO. Full 
manuscripts are planned to be submitted for the baseline data and for final data. Single country 
reports may be published as soon as they are available. The joint-safety analysis after 18 months 
(i.e. the combined analysis with safety data from the ETNA-AF PASS; see also Section 9.7) will 
be submitted to the PRAC. In addition, PRAC will receive a summary of the progress of the study 
as part of the PSURs. 
 

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13. 
DOCUMENTATION AND ARCHIVING 
The sponsor is responsible for archiving study specific documentation (Observational Plan, 
amendments, copy of eCRF burned on CD, Final Report and Database) for at least ten years. 
Archived data may be held on electronic record, provided that a back-up exists and that hard copies 
can be obtained, if required. 
The investigator is responsible for archiving the patient identification list, all signed ICFs, copy of 
his eCRF burned on a CD, and his contract for at least ten years and in accordance with local 
legislation. 
Physicians are obliged to keep patient files according to national requirements. 
 

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14. 
LEGAL REQUIREMENTS 
This PASS will be conducted according to the rules of Good Pharmacoepidemiology Practice 
(GPP) and the Guideline on Good Pharmacovigilance Practices (GVP), Module VIII (Rev 1) 
EMA/813938/2011 Rev 1 and the Declaration of Helsinki and will be conducted in accordance 
with the respective standard operating procedures (SOPs) of DSE. 
 
14.1. 
Reimbursement 
Compensation according to local regulations and to the time spent to inform patients and to 
document patient data will be paid two times a year if not specified otherwise in the site contract. 
This compensation also includes the honorarium for responding to queries, the ongoing reporting 
of edoxaban related ADRs and for onsite monitoring data collection points. 
 
14.2. 
Registration 
This study will be listed in in the EU-PAS register and a public study database which meets 
International Committee of Medical Journal Editors requirements.  
 

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15. 
FINAL REPORT  
A final report will be presented at the latest 6 months after LPO, if not required earlier by local 
legislation. It will be prepared according to the specific guidelines for PASS reports provided by 
the EMA.  
 

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16. 
PUBLICATION 
In order to protect confidential information and/or the interests of DSE, all publications 
(manuscripts and congress presentations) or announcements originating from this research are 
governed jointly by the SC and the sponsor.  
Aside from the main publication, participating investigators in the study can propose subgroup 
analysis and related second level publications to the SC and the sponsor. Such publications may 
be produced by a dedicated team of authors other than the SC in common agreement with and 
governed jointly by the SC and the sponsor.  
 

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17. 
PREMATURE TERMINATION OF THE PASS 
In the case of a premature termination of the entire PASS by the sponsor, the project leader has to 
inform all participating sites, Ethics Committees, and authorities including PRAC. In case the 
PASS is terminated by the authorities, the project leader informs all participating sites and Ethics 
Committees. 
 
 

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18. 
REFERENCES 
 
1. Goldhaber Z and Bounameaux H. Pulmonary embolism and deep vein thrombosis. 
Lancet 2012; 379: 1835-46. 
2. Cohen AT et al. Venous thromboembolism in Europe. Thromb Haemost 2007; 98: 756-
64. 
3. Giugliano RP, Ruff CT, Braunwald E, et al. Once-daily Edoxaban versus warfarin in 
patients with atrial fibrillation. N Engl J Med 2013; 3 69 (22): 2093–104. 
4. Ruff CT et al. Evaluation of the novel factor Xa inhibitor Edoxaban compared with 
warfarin in patients with atrial fibrillation: Design and rationale for the Effective 
aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In 
Myocardial Infarction study 48 (ENGAGE AF–TIMI 48). Am Heart J 2010; 160: 635-
641.e2. 
5. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic 
venous thromboembolism. N Engl J Med 2013; 369:1406-15. 
6. Bounameaux H, Camm AJ. Edoxaban: An update on the new oral direct FXa Inhibitor. 
Drugs. 2014; 74 (11): 1209-31. 
7. Agnelli G, Gitt A, Bauersache R, et al. The management of acute venous 
thromboembolism in clinical practice – study rationale and protocol of the European 
PREFER in VTE Registry. Thrombosis J 2015; 13:41. 
8. Monreal M et al. Management of patients with acute venous thromboembolism: findings 
from the RIETE registry. Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-
6):330-4. 
 
 
 

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APPENDIX 1. LIST OF STAND-ALONE DOCUMENTS 
 
Informed Consent Form (ICF) – English master template 
Site Qualification Questionnaire – English master template 
Site list (to be added after site selection process is finished) 
SmPC for edoxaban 
eCRF and corresponding manual in local language 
Patient Memory Aid – English master 
Steering Committee Charter (draft) 
Event Adjudication Committee Charter (draft) 
Statistical Analysis Plans(SAP)  
Data Management Plan (DMP)  
(S)ADR Reconciliation Plan  
Clinical Operations Plan (COP) 
 
 
 

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APPENDIX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
 

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