A Pilot Study on Edoxaban for the Resolution of Left Atrial Thrombosis in Patients With Non-valvular Atrial Fibrillation
Phase: PHASE2
Conditions: Atrial Fibrillation
Sponsor: Raffaele De Caterina

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CLINICAL STUDY PROTOCOL 
 
 
A pilot study on Edoxaban for the resolution of left atrial thrombosis  
in patients with non-valvular atrial fibrillation 
 
  
 
Study code: 
EudraCT Number: 
 
 
Promoter: 
 
 
 
 
Coordinating investigator : 
 
 
 
 
 
 
Version and date: 
 
EDO-SP-01-2015 
2015-004847-37 
 
 
Fondazione Gabriele d’Annunzio 
Via dei Vestini, 31 
66100 Chieti 
 
 
Prof. Raffaele De Caterina 
Università degli Studi G. d’Annunzio 
Via dei Vestini 
66013 Chieti 
E-mail: rdecater@unich.it 
 
 
Ver. 4.0 (18 Sept 2017) 
 
The present protocol contains confidential information that is the property of the Sponsor, Fondazione Gabriele 
d’Annunzio - Chieti. This information is given for the needs of the study and must not be disclosed without prior 
written consent of the Fondazione Gabriele d’Annunzio - Chieti. Persons to whom this information is given for the 
needs of the study must be informed that it is confidential and must not be disclosed. 
 
 

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PROTOCOL SIGNATURE PAGE 
 
Version 4.0 – 18 Sept 2017 
 
 
Promoter’s approval 
 
___________________________________ 
 
__________________________________ 
Qualification 
 
Name (Block letters) 
 
___________________________________ 
__________________________________ 
Date 
 
Signature 
 
 
 
Investigator’s agreement 
I have discussed the objectives of this trial and the contents of this protocol with the Promoter’s 
representative. I understand that the information in this protocol is confidential and should not 
be disclosed, other than to those directly involved in the execution of the ethical review of the 
study, without written authorisation from Fondazione Gabriele d’Annunzio di Chieti. It is, 
however, permissible to provide information to a subject in order to obtain consent. 
I agree to conduct the trial according to this protocol and to comply with its requirements, subject 
to ethical and safety requirements and guidelines, and to conduct the trial according to ICH 
guidelines on GCP and with the applicable regulatory requirements. 
I understand that the Promoter may decide to suspend or prematurely terminate the trial at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the trial I will communicate my intention 
immediately in writing to the Promoter. 
 
 
___________________________________ 
 
 
__________________________________ 
Qualification 
 
Principal Investigator name (Block letters) 
 
___________________________________ 
__________________________________ 
Date 
 
Signature 
 
 
 
 

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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1.1. 
SYNOPSYS ....................................................................................................................... 6 
1.2. 
LIST OF ABBREVIATIONS ............................................................................................... 10 
2.1. 
TARGET PATHOLOGY AND THERAPY ............................................................................ 11 
2.2. 
TARGET PATHOLOGY DEFINITION ................................................................................ 12 
2.3. 
INFORMATION ON THE TEST PRODUCT ....................................................................... 12 
2.4. 
STUDY RATIONALE ........................................................................................................ 13 
2.5. 
OVERALL RISK AND BENEFIT ASSESSMENT .................................................................. 13 
3.1. 
PRIMARY OBJECTIVE ..................................................................................................... 15 
3.2. 
SECONDARY OBJECTIVE(S)............................................................................................ 15 
5.1. 
OVERALL DESCRIPTION ................................................................................................. 16 
5.2. 
DISCUSSION OF THE STUDY DESIGN............................................................................. 16 
5.2.1. 
Choice of the Study Population ................................................................................. 16 
5.2.2. 
Choice of the Study Design ........................................................................................ 16 
5.2.3. 
Choice of the Sample Size and the number of centres ............................................. 16 
5.3. 
STUDY PERIOD .............................................................................................................. 17 
6.1. 
INCLUSION CRITERIA .................................................................................................... 17 
6.2. 
EXCLUSION CRITERIA .................................................................................................... 18 
6.3. 
WITHDRAWAL AND /EARLY DISCONTINUATION CRITERIA .......................................... 19 
7.1. 
PACKAGING AND LABELLING ........................................................................................ 20 
7.2. 
DRUG ADMINISTRATION .............................................................................................. 21 
7.3. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF INVESTIGATIONAL 
PRODUCT(S) .................................................................................................................. 21 
9.1. 
EFFICACY ASSESSMENT ................................................................................................ 22 
9.1.1. 
Primary endpoint ....................................................................................................... 22 
9.1.2. 
Secondary endpoint .................................................................................................. 22 
9.2. 
SAFETY ASSESSMENT .................................................................................................... 22 
9.2.1. 
Definition of major bleeding ..................................................................................... 23 
9.2.2. 
Non-major bleeding ................................................................................................... 23 
9.2.3. 
Stroke and thrombotic events ................................................................................... 23 
9.2.4. 
Adverse Events .......................................................................................................... 24 
9.3. 
COMPLIANCE ................................................................................................................ 24 
10.1. BASELINE VISIT .............................................................................................................. 25 
10.2. FOLLOW-UP (WEEK 4) .................................................................................................. 25 
10.3. FINAL TELEPHONE ASSESSMENT (WEEK 8) .................................................................. 26 
10.4. ASSESSMENTS AND PROCEDURES ................................................................................ 26 

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10.4.1. Stroke risk index ........................................................................................................ 26 
10.4.2. Bleeding risk index ..................................................................................................... 26 
11.1. ADVERSE EVENTS .......................................................................................................... 27 
11.1.1. Definition of Adverse Events ..................................................................................... 27 
11.1.2. Grading of Adverse Events ........................................................................................ 27 
11.1.3. Reporting of Adverse Events ..................................................................................... 27 
11.2. SERIOUS ADVERSE EVENTS (SAE) ................................................................................. 28 
11.2.1. Definition ................................................................................................................... 28 
11.2.2. Reporting of SAE ........................................................................................................ 28 
11.2.3. Follow-up of SAE ........................................................................................................ 29 
11.2.4. SAE Occurring After the Study ................................................................................... 29 
12.1. DATA COLLECTION ........................................................................................................ 30 
12.1.1. Case Report Form ...................................................................................................... 30 
12.1.2. Source Documents .................................................................................................... 30 
12.2. STUDY MONITORING .................................................................................................... 30 
12.2.1. Monitoring visits ........................................................................................................ 30 
12.2.2. Direct Access to Source Documents .......................................................................... 31 
13.1. DATA ENTRY.................................................................................................................. 31 
13.2. DATA CLEANING ........................................................................................................... 31 
13.3. DATA CODING ............................................................................................................... 32 
13.4. DATABASE LOCK ........................................................................................................... 32 
14.1. GENERAL CONSIDERATIONS ......................................................................................... 32 
14.2. SAMPLE SIZE ................................................................................................................. 32 
14.3. PROTOCOL DEVIATIONS ............................................................................................... 33 
14.4. DATA SETS ANALYSIS .................................................................................................... 33 
14.5. HANDLING OF DROPOUTS AND MISSING DATA .......................................................... 34 
14.5.1. Dropouts and Missing Data ....................................................................................... 34 
14.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................................... 34 
14.7. EFFICACY ANALYSIS ...................................................................................................... 34 
14.7.1. Primary Criterion ....................................................................................................... 34 
14.7.2. Secondary Criteria ..................................................................................................... 35 
14.8. SAFETY ANALYSIS .......................................................................................................... 35 
14.8.1. Adverse Events .......................................................................................................... 36 
14.8.2. Concomitant treatments ........................................................................................... 36 
14.9. COMPLIANCE ................................................................................................................ 37 
14.10. INTERIM ANALYSIS AND DATA MONITORING .............................................................. 37 
14.11. ETHICAL CONDITIONS ................................................................................................... 37 
14.12. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ....................................................... 37 

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14.13. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT FORM ....................... 38 
14.14. PERSONAL DATA PROTECTION ..................................................................................... 38 
14.15. INSURANCE POLICY....................................................................................................... 39 
15.1. PROTOCOL AMENDMENT ............................................................................................. 39 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE .............................................. 39 
15.3. END OF THE STUDY ....................................................................................................... 40 
15.3.1. Definition of the End of Study ................................................................................... 40 
15.3.2. Early Study Termination ............................................................................................ 40 
15.3.2.1. Early Study Termination Decided by the Sponsor .................................................. 40 
15.3.2.2. Early Study Termination Decided by the Competent Authorities .......................... 40 
15.4. AUDIT ............................................................................................................................ 41 
15.5. INSPECTION .................................................................................................................. 41 
15.6. CONFIDENTIALITY ......................................................................................................... 41 
15.7. STUDY RESULTS PUBLICATION ..................................................................................... 41 
16.1. BIBLIOGRAPHY .............................................................................................................. 42 
17.1. APPENDIX A - DECLARATION OF HELSINKI ................................................................... 44 
17.2. APPENDIX B - SAE FORM .............................................................................................. 48 
 
 
 

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1.1. 
SYNOPSYS 
 
 
Name of Sponsor: 
Fondazione Gabriele d’Annunzio - Chieti 
Name of Finished 
Product: 
Lixiana 
Name of Active 
Substance:  
Edoxaban 
Title of the Study: 
A pilot study on Edoxaban for the resolution of left atrial thrombosis in patients with 
non-valvular atrial fibrillation 
 
Abbreviated Title: 
Edoxaban in AF 
Study Coordinating 
Investigator: 
Prof. Raffaele De Caterina 
Study Centres: 
A total of 6-8 Italian sites will be involved. 
 
Background 
Current guidelines indicate a ≥3 weeks therapy with VKAs to allow the resolution of 
LA or LAA thrombus in patients with atrial fibrillation before cardioversion.  
Rationale: 
Isolated reports have indicated that complete LA or LAA thrombus resolution may be 
achieved also with use of oral Factor Xa inhibitors, which have demonstrated the same 
efficacy but a better safety profile compared to warfarin. 
The aim of this open-label pilot study is to investigate the percentage of LA/LAA 
thrombus resolution with edoxaban therapy in patients with non-valvular atrial 
fibrillation. The subordinated aim is the design a larger and longer study to compare 
edoxaban and warfarin in the same patient population. 
Planned Study Period: 
Start of enrolment: November 2017  
End of enrolment: February 2019 
Clinical Phase: Phase 2 
 
Objectives: 
 
The primary objective of the study will be the definition of the percentage of patients 
who, after 4 weeks of edoxaban treatment, will experience complete thrombus 
resolution by TEE. 
Secondary objectives will be the assessment of bleeding events after 4 weeks of 
treatment with edoxaban and, after the same period, the incidence of any stroke or 
peripheral embolism and the time, when applicable, to electrical cardio-version. 
Methodology: 
Non-controlled, open-label, 4 weeks pilot study. 
 
Number of patients: 
A total of 25 patients will be included in the study. 
Diagnosis and Criteria for 
Inclusion: 
Inclusion criteria 
Patients with all the following criteria will be eligible for inclusion in the study 
protocol: 
1. Signed written informed consent. 
2. Males and females ≥ 18 years of age. 
3. Female subjects must be post-menopausal (for at least 2 years), surgically 
sterile, abstinent, or, if sexually active, be practicing an effective method of birth 
control (e.g., prescription oral contraceptives, contraceptive injections, 
intrauterine device, double-barrier method, contraceptive patch, male partner 
sterilization) before entry and throughout the study; and, for those of 

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childbearing potential, have a negative serum β-hCG pregnancy test at 
screening. 
4. Atrial fibrillation (AF) must be documented by ECG evidence (e.g., 12-lead ECG, 
rhythm strip, Holter, pacemaker interrogation) within 30 days before enrolment. 
5. Subjects with newly diagnosed atrial fibrillation are eligible provided that: 
 
-there is evidence that the atrial fibrillation is non-valvular: 
 
-there is ECG evidence on 2 occasions 24 hours apart demonstrating atrial 
fibrillation. 
6. LA or LAA thrombosis  documented by trans-esophageal echocardiography (TEE)  
7. CHA2DS2-VASC score >1. 
  
Exclusion criteria 
Patients with all the following criteria will not be eligible for inclusion in the study 
protocol: 
1. Hemodynamically significant mitral valve stenosis. 
2. Prosthetic heart mechanical or biological valve (annuloplasty with or without 
prosthetic ring, commissurotomy and/or valvuloplasty are permitted). 
3. Transient atrial fibrillation caused by a reversible disorder (e.g., thyrotoxicosis, 
pulmonary embolism, recent surgery or myocardial infarction). 
4. Known presence of atrial myxoma. 
5. Left ventricular thrombus. 
6. Active endocarditis. 
7. Active internal bleeding. 
8. History of condition associated with increased bleeding risk including, but not 
limited to: 
 
 major surgical procedure or trauma within 30 days; 
 
clinically significant gastrointestinal bleeding within 6 months; 
 
previous intracranial, intraocular, spinal, atraumatic intra-articular bleeding; 
 
chronic haemorrhagic disorder; 
 
Any neoplasm, including intracranial neoplasm, 
 
arteriovenous malformation or aneurysm. 
9. Platelet count <90,000/μL at the screening visit. 
10. Sustained uncontrolled hypertension: SBP ≥180 mmHg or DBP ≥100 mmHg. 
11. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive within 3 
months or any stroke < 14 days). 
12. Transient ischemic attack within 3 days. 
13. Any oral anticoagulant therapy at the time of the baseline visit. 
14. Treatment with: 
 
aspirin >160 mg daily; 
 
aspirin plus a thienopyridine within 5 days; 
 
intravenous antiplatelets within 5 days; 
 
fibrinolytics within 10 days. 
15. Anticipated need for therapy with a non-steroidal anti-inflammatory drug in the 
next 4 weeks. 
16. Treatment with a strong inducer of cytochrome P450 and P glycoprotein, such 
as ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, lopinavir, 

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telaprevir, indinavir, conivaptan, claritromycin or planned treatment during the 
study. 
17. Other indication for anticoagulant therapy. 
18. Hypersensitivity or intolerance to the study drug, including excipients. 
19. Women of childbearing potential who do not want adopt a contraceptive 
method during the study period and the following 4 weeks. 
20. Breast-feeding women during the study period and the following 4 weeks. 
21. Anemia (hemoglobin <10 g/dL) at the screening visit. 
22. Known significant liver disease (e.g., acute clinical hepatitis, chronic active 
hepatitis, cirrhosis), or ALT or AST  >2 x ULN or total bilirubin >1.5 x ULN. 
23. Patients with moderate or severe renal impairment (CrCL <50 mL/min) or 
patients with end stage renal disease (CrCL < 15 mL/min) or on dialysis. 
Test Product, dose and 
duration of treatment 
All patients will receive edoxaban 60 mg once a day, with open-label design, for 4 
weeks. Edoxaban daily dose will be reduced to 30 mg/day in case of: body weight ≤60 
kg, or concomitant therapy with verapamil/quinidine/dronedarone. 
Statistical Methods: 
Sample Size 
There are no previous studies conducted with edoxaban on atrial thrombus 
dissolution and this is a pilot trial. For this reason sample size has been determined 
empirically, on the basis of case reports with similar products in this clinical conditions 
(6, 8-10, 15). However, if the proportion of patients with thrombus dissolution after 4 
weeks of treatment will be 60%, which is compatible with the above mentioned case 
reports, a sample size of 25 produces a two-sided 95% confidence interval with range 
39-79%. 
 
Primary Analysis 
Primary outcome will be the detection of the percentage of patients, after 4 weeks 
of edoxaban treatment, with complete thrombus resolution by TEE, evaluated with 
the following Probe angulations: 0°, 45°-to-60°, 90°. As this is a single arm, open-
label study, in principle, only a descriptive statistical analysis will be performed for 
the primary criterion. 
 
Secondary analyses 
Secondary endpoints will be: absolute and percent variation of thrombus area at 4 
weeks by TEE evaluation (Probe angulations: 0°, 45-to-60°, 90°) and time to electrical 
cardio-version (when applicable). Only a descriptive statistical analysis will be 
performed for the secondary criterion. 
 
Safety analysis 
Analyses of the safety criteria that will include: percentage of bleeding events at 4 
weeks and after 8 weeks (telephone assessment) after the end of the treatment; 
percentage of any stroke or peripheral embolism at 4 weeks and after 8 weeks 
(telephone assessment) after the end of the treatment; percentage of any other safety 
related events (deaths, SAEs and AEs). 
 
 
 
 

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Study flow-chart 
 
 
 
BASELINE 
FOLLOW-UP 
PHONE 
ASSESSMENT 
 
Timing 
Day 0 
 
Week 4 
(+ 3 days) 
Week 8 
(+ 3 days) 
Confirmation of consent  

 
 
Verification of inclusion/exclusion criteria 
 
 
 
Demographic data 
 
 
 
Medical history 
 
 

CHA2DS2-VASC score and HAS-BLED score 
 
 

Information regarding AF 
 
 
 
Blood pressure, heart rate 
 
 
 
EKG 
 
 
 
Transthoracic echocardiogram 
 
 
 
Transesophageal echocardiogram 
 
 
 
Blood count; liver and renal function 
 
 

Concomitant treatments 
 
 

Bleeding events 
 
 

Thromboembolic events 
 
 

Other adverse events 
 
 

Study drug dispensation 
 
 

Compliance 
 
 

Study completion form 
 
 

 
 
 

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1.2. 
LIST OF ABBREVIATIONS 
 
 
ADR 
: Adverse Drug Reaction 
AE 
: Adverse Event 
AF 
: Atrial Fibrillation 
ALT 
: Alanine aminotransferase 
AST 
: Aspartate aminotransferase 
ATC 
: Anatomical Therapeutic Chemical Classification System 
CHA2DS2 
: Cardiac failure, Hypertension, Age (x2 ), Diabetes, Stroke (x 2)  risk index 
CI 
: Confidence Interval 
CRA 
: Clinical Research Associate 
CRF 
: Case Report Form 
DBP 
: Diastolic Blood Pressure 
EC 
: Ethic Committee 
ECG 
: Electrocardiogram 
FAS 
: Full Analysis Set 
GCP 
: Good Clinical Practice 
HR 
: Hazard Ratio 
ICH 
: International Conference on Harmonisation 
LA 
: Left Atrial 
LAA 
: Left Atrial Appendage 
MedDRA 
: Medical Dictionary for Regulatory Activities 
NOAC 
: Non vitamin K oral anticoagulants 
OAC 
: Oral Anticoagulant Therapy 
PP 
: Per Protocol 
SAE 
: Serious Adverse Event 
SBP 
: Systolic Blood Pressure 
SEE 
: Systemic Embolic Events 
SmPC 
: Summary of Product Characteristics 
TEE 
: Trans Esophageal Echocardiography 
ULN 
: Upper Level of Normal 
VKA 
: vitamin K antagonists 
WHO 
: World Health Organization 
 
 
 

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2. INTRODUCTION AND STUDY RATIONALE 
 
2.1. 
TARGET PATHOLOGY AND THERAPY 
It is estimated that atrial fibrillation (AF) affects up to 2% of the general Western World 
population, and up to 5% of acute stroke patients. The lifetime risk of developing an episode of 
AF is up to 25% in those who have reached the age of 40 (1). 
AF is associated with increased rates of death, stroke and other thromboembolic events. Death 
rates are doubled by AF, whereas stroke is often severe and results in long-term disability. It is 
estimated that about 20% of stroke is due to AF (1). Moreover, hospitalizations due to 
thromboembolic complications and progressive cognitive dysfunction due to asymptomatic 
embolic events are also ascribed to AF (1). 
Current guidelines indicate a ≥3 weeks therapy with vitamin K antagonists (VKAs) to allow the 
resolution of left atrial (LA) or left atrial appendage (LAA) thrombus in patients with atrial 
fibrillation (1) before cardioversion.  
The presence of LA and LAA thrombi is usually detected by transesophageal echocardiography 
(TEE). When thrombus is detected, the percentages of thrombus resolution with VKAs vary, in 
various studies, from 55% to 85%  usually in 4 weeks time (2-5). Such range is at least in part 
related to the level of anticoagulant activity obtained, and resolution likely depends on optimal 
anticoagulation intensity under VKA treatment, which is sub-optimal in the induction phase of 
VKA treatment. 
Isolated reports (6, 15) have indicated that complete LA or LAA thrombus resolution may be 
achieved with the use of oral Factor Xa inhibitors, which in randomized trials were non-inferior 
to warfarin with regard to the incidence of the primary outcome measure (7), including any 
stroke or peripheral embolism in patients with non-valvular atrial fibrillation, but also ensure 
immediate and stable anticoagulation. Oral Factor Xa inhibitors have also demonstrated a 
better safety profile than warfarin. 

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2.2. 
TARGET PATHOLOGY DEFINITION 
Non-valvular atrial fibrillation in patient with high atrial fibrillation-related thromboembolic 
risk, and LA or LAA thrombosis. 
2.3. 
INFORMATION ON THE TEST PRODUCT 
Edoxaban is an oral direct factor-Xa inhibitor similar to the previously developed molecules 
rivaroxaban and apixaban. 
As reported in the approved SmPC, both animal and Phase I studies have demonstrated that 
edoxaban is highly effective in factor Xa-inhibition activity and reducing clot formation. In rat 
and monkey models, edoxaban demonstrated almost complete inhibition of factor-Xa activity 
and (in particular in monkeys) a rapid onset of inhibitory effect. 
Edoxaban quickly reaches peak plasma concentrations in 1.5 hours; its half-life is between 10 
and 14 hours. Oral bioavailability is quite high (more than 62%) and factor-Xa inhibition is highly 
selective, competitive, and concentration-dependent. Plasma concentrations of edoxaban are 
also closely correlated with the suppression of other coagulation indices and various platelet-
activation parameters. 
The results for all-cause mortality in the pivotal study ENGAGE AF-TIMI 48 study were 769 
(3.99% per year) for subjects taking edoxaban 60 mg as opposed to 836 (4.35% per year) for 
warfarin [HR (95% CI): 0.91 (0.83 - 1.01)]. 
In the same study there was a significantly lower rate in favour of the edoxaban 60 mg 
treatment group compared with the warfarin group of major bleeding (2.75%, and 3.43% per 
year, respectively) [HR (95% CI): 0.80 (0.71,-  0.91); p = 0.0009], and intracranial  hemorrhage 
(0.39%, and 0.85%  per year, respectively) [HR (95% CI): 0.47 (0.34 - 0.63); p < 0.0001].  
The lower rates of fatal bleeds were also significant for the edoxaban 60 mg treatment group 
compared with the warfarin group (0.21%, and 0.38%) [HR (95 % CI): 0. 55 (0.36 - 0.84); p = 

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0.0059 for superiority], primarily because of the reduction in fatal Intracranial haemorrhage 
bleeds [HR  (95% CI): 0.58 (0.35 - 0.95); p = 0.0312]. 
 
2.4. 
STUDY RATIONALE 
The aim of this open-label pilot study is to investigate the extent of LA/LAA thrombus resolution 
with edoxaban therapy in patients with non-valvular atrial fibrillation. 
A subordinated aim of this study is the planning and design of a larger study directly comparing 
edoxaban vs warfarin in the same patient population. With the exception of few case reports, 
there are no data in the same patient population referred to antithrombotic treatments other 
than vitamin K antagonists.  
As the main goal of this exploratory study is the estimation of the magnitude of the LA/LAA 
thrombus resolution with edoxaban, no control group with vitamin K antagonists has been 
considered, providing that, for the purpose of this study, the magnitude of the response of 
warfarin is satisfactory defined (1). 
 
2.5. 
OVERALL RISK AND BENEFIT ASSESSMENT 
 
Anticoagulant therapy is anyway necessary for the population under study 
Patients with AF have an increased risk of recurrent embolism, and therefore should receive 
anticoagulant therapy. In particular, for patients with CHA2DS2-VASc score >1 the Guidelines for 
the management of atrial fibrillation (1) recommend an anticoagulant therapy in any case. 
Either oral anticoagulant therapy (OAC), including non-vitamin K oral anticoagulants (NOACs), 
or aspirin 75–325 mg daily are recommended, with preference of OAC to aspirin. 

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No use of placebo 
Placebo is not used in this study, neither as a comparative agent nor as an add-on agent, in the 
cohort of patients under study. 
Edoxaban is safer than warfarin 
In the pivotal ENGAGE AF-TIMI 48 study (7) it has been demonstrated that more than half of 
the lower rates of all-cause deaths with edoxaban as compared to warfarin were directly 
attributable to fewer fatal bleeding events and non-fatal major bleeding that contributed to a 
death within 30 days. There were no differences between edoxaban and warfarin in deaths due 
to non-cardiovascular causes, nor for any of the 3 most common cardiovascular causes of death, 
sudden cardiac death, heart failure, ischemic stroke. However, warfarin was associated with 
approximately twice the risk of fatal bleeding as compared to edoxaban 
Positive results with other NOACs 
There have been few recent case reports  about  the  resolution  of  LAA  thrombus  in  patients  
treated with  NOACs (6, 8-10), showing  disappearance  of thrombi after very 5 weeks or less of 
NOACs treatment, and consistently suggesting that such therapy might be effective the this 
clinical condition. 
Summary of risk and benefit assessment 
Taking into account all medical needs, the positive safety data of edoxaban compared to 
warfarin, and the encouraging efficacy data from drugs belonging to the same class, it can be 
reasonably concluded that the participation to this study does not expose the patient to 
unforeseen risks. 
 

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3. STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective of the study will be the definition of the extent of patients who, after 4 
weeks of edoxaban treatment, will experience complete thrombus resolution by TEE. 
 
3.2. 
SECONDARY OBJECTIVE(S) 
Secondary objectives will be the assessment of bleeding events after 4 weeks of treatment with 
edoxaban and, after the same period, the incidence of any stroke or peripheral embolism and 
the time, when applicable, to electrical cardioversion. 
 
4. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial will be conducted according to Good Clinical Practices (CPMP/ICH/135/95), as well as 
the Declaration of Helsinki and its subsequent amendments (see Appendix) and national 
regulations. This protocol and related documents (included the informed consent form) will be 
submitted for approval to independent local Ethics Committees before the study set up, 
according to national regulations. 
All the protocol amendments or critical events liable to increase the risks incurred by the 
subjects or to compromise the validity of the study or subjects' rights will be submitted to the 
Coordinator, the concerned Authorities and the Ethics Committees. 
After being informed orally and in writing of all aspects and constraints of the trial, as well as of 
their freedom to withdraw their participation at any time, patients will sign a consent form. A 
time for informed reflection on the protocol will be given to each patient before they give 
written consent and before starting the study procedures. 
Patients will be made aware of their rights to decline to participate or to withdraw from the 
study at any time. 

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This study does not involve the use of placebo. 
5. STUDY DESIGN 
5.1. 
OVERALL DESCRIPTION 
This is a pilot, non-controlled, open-label, 4-weeks study. 
5.2. DISCUSSION OF THE STUDY DESIGN 
5.2.1. Choice of the Study Population 
A total of 25 patients with non-valvular atrial fibrillation, high atrial fibrillation-related stroke 
risk, and documented LA or LAA thrombosis will be included in the study. 
5.2.2. Choice of the Study Design 
With the exception of some case reports (6, 15), there are no studies conducted with NOACs to 
assess their efficacy in the resolution of non-valvular atrial thrombi once they are formed in the 
atria. For this reason, this study was designed to get preliminary clinical indications in order to 
is plan a larger study directly comparing edoxaban and warfarin in the same patient population. 
Due to its exploratory objective, no control group will be considered. Duration of the study is 
consistent with recommendations given by the guidelines, and with the reported clinical 
experiences (1, 6, 8-10, 15). 
5.2.3. Choice of the Sample Size and the number of centres 
There are no previous studies conducted with edoxaban on atrial thrombus dissolution, and this 
is a pilot trial. For this reason, sample size has been determined empirically, on the basis of case 
reports with similar products in this clinical conditions (6, 8-10, 15) and better described in 
section 14. 
The involvement of 6-8 sites implies an enrolment of an average of about 4 patient per site to 
be recruited in about 15 months. 

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5.3. 
STUDY PERIOD 
The planned start of enrolment is November 2017. The total duration of the enrolment phase 
is supposed to be 15 months and therefore the completion of the recruitment is expected by 
February 2019. 
The last patient visit is expected by September 2018. 
6. STUDY POPULATION 
In this pilot study a total of 25 patients with non-valvular atrial fibrillation, high atrial fibrillation-
related stroke risk and LA or LAA thrombosis will be recruited. 
 
6.1. 
INCLUSION CRITERIA 
Patients with all the following criteria will be eligible for inclusion in the study protocol: 
1.  
Signed written informed consent 
2. Males and females ≥ 18 years of age 
3. Female subjects must be postmenopausal (for at least 2 years), surgically sterile, 
abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., 
prescription oral contraceptives, contraceptive injections, intrauterine device, double-
barrier method, contraceptive patch, male partner sterilization) before entry and 
throughout the study; and, for those of childbearing potential, have a negative serum β-
hCG pregnancy test at screening 
4. Atrial fibrillation (AF) must be documented by ECG evidence (e.g., 12-lead ECG, rhythm 
strip, Holter, pacemaker interrogation) within 30 days before enrolment. 
5.  
Subjects with newly diagnosed atrial fibrillation are eligible provided that: 
a. there is evidence that the atrial fibrillation is non-valvular 
b. there is ECG evidence on 2 occasions 24 hours apart, demonstrating atrial 
fibrillation 
6. LA or LAA thrombosis  documented by transesophageal echocardiography (TEE)  

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7. CHA2DS2-VASC score >1. 
 
6.2. 
EXCLUSION CRITERIA 
Patients with all the following criteria will not be eligible for inclusion in the study protocol: 
Cardiac-related conditions 
1. Hemodynamically significant mitral valve stenosis 
2. Mechanical or biological prosthetic heart valve (annuloplasty with or without prosthetic 
ring, commissurotomy and/or valvuloplasty are permitted) 
3. Transient atrial fibrillation caused by a reversible disorder (e.g., thyrotoxicosis, 
pulmonary embolism, recent surgery or myocardial infarction) 
4.  
Known presence of atrial myxoma 
5. Left ventricular thrombus 
6. Active endocarditis. 
 
Bleeding risk-related criteria 
7. Active internal bleeding. 
8. History of condition associated with increased bleeding risk including, but not limited 
to: 
a.  major surgical procedure or trauma within 30 days 
b. clinically significant gastrointestinal bleeding within 6 months 
c. previous intracranial, intraocular, spinal, atraumatic intra-articular bleeding 
d. chronic hemorrhagic disorders 
e. Any neoplasm, including intracranial neoplasm 
f. Arterio-venous malformation or aneurysm. 
9. Platelet count <90,000/μL at the screening visit 
10.  
Sustained uncontrolled hypertension: SBP ≥180 mmHg or DBP ≥100 mmHg 
11. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive within 3 months or 
any stroke < 14 days) 
12.  
Transient ischemic attack within 3 days. 
 
Concomitant or intercurrent therapies 

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13. Any oral anticoagulant therapy at the time of the baseline visit 
14. Treatment with: 
a. aspirin >160 mg daily 
b. aspirin plus a thienopyridine within 5 days 
c. intravenous antiplatelets within 5 days 
d. fibrinolytics within 10 days. 
15.  
Anticipated need for therapy with a non-steroidal anti-inflammatory drug in the 
next 4 weeks 
16.  
Treatment with a strong inducer of cytochrome P450 and P glycoprotein, such as 
ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, lopinavir, telaprevir, 
indinavir, conivaptan, claritromycin or planned treatment during the study 
17.  
Other indications for anticoagulant therapy 
18. Hypersensitivity or intolerance to the study drug, including excipients. 
 
Other concomitant or intercurrent conditions 
19. Women of childbearing potential who do not want adopt a contraceptive method during 
the study period and the following 4 weeks 
20. Breast-feeding women during the study period and the following 4 weeks 
21.  
Anemia (hemoglobin <10 g/dL) at the screening visit 
22.  
Known significant liver disease (e.g., acute clinical hepatitis, chronic active 
hepatitis, cirrhosis), or ALT or AST  >2 x ULN or total bilirubin >1.5 x ULN 
23. Patients with moderate or severe renal impairment (CrCL <50 mL/min) or patients with 
end stage renal disease (CrCL < 15 mL/min) or on dialysis. 
 
6.3. 
WITHDRAWAL AND /EARLY DISCONTINUATION CRITERIA 
In addition to screening failure, the reasons for a patient's premature withdrawal or early 
discontinuation from the study may be the following: 
 The patient’s or legal representative’s decision that can occur for any reason and at any 
time 

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 The Investigator's decision in the patient's interest. Particularly, if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient 
 An erroneous inclusionaccording to the protocol. The decision to maintain the patient or 
not in the study will be taken jointly by the Investigator and the Promoter 
 Promoter’s or Competent Authorities’ motivated decision 
 Other reasons, to be specified, such as: death, adverse events, lack of efficacy, major 
protocol violation, non-compliance, pregnancy, loss at follow-up. 
The Investigator should attempt to collect, as soon as possible, the following information for a 
final assessment: 
o reason(s) for withdrawal to be reported in the case report form 
o evaluation of the patient's clinical condition 
o if necessary, take appropriate therapeutic measures: management of an adverse 
effect or concomitant disease, prescription of another treatment 
o recover the investigational product previously given to the patient. 
In all cases, available data will be kept for the safety analysis. 
 
7. STUDY TREATMENT 
All patients will receive edoxaban 60 mg once a day, with an open-label design, for 4 weeks. 
Edoxaban daily dose will be reduced to 30 mg/day in case of: body weight ≤60 kg, or 
concomitant therapy with verapamil/quinidine/dronedarone. 
 
7.1. 
PACKAGING AND LABELLING 
The treatment units will be the commercial product manufactured by Daiichi Sankyo. It is 
dispensed in form of film-coated tablets and packed in blisters. 

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The commercial outer boxes will be labelled according to European Directives and local 
requirements. 
At the baseline visit, the Investigator will provide the patients with the medications necessary 
to complete treatment until the next follow-up visit. 
 
7.2. 
DRUG ADMINISTRATION 
One tablet daily to be taken as a whole with some water, with or without food, for a period of 
28 days. 
 
7.3. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF INVESTIGATIONAL 
PRODUCT(S)  
The Investigator should maintain accurate written records of drugs received, dispensed, 
returned and any remaining treatment units, on the drug accountability form. The packaging of 
the medication should remain intact until just before the dispensation. 
At the end of the study, all used and unused treatments including packaging should be noted, 
and local destruction or return is organised by the appointed CRA. A copy of the drug 
accountability form should be provided by the Investigator to the CRA. 
 
8. CONCOMITANT TREATMENTS 
Any existing concomitant treatment, any new concomitant treatment or change in the dosage 
of an existing concomitant treatment during the course of the study must be noted on the CRF. 
For all concomitant treatments taken during the study, the following information must be noted 
in the relevant section(s) of the CRF: 

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 The name of the treatment and its form 
 The reason for prescription 
 The route of administration 
 The daily dose 
 The duration. 
9. EVALUATION CRITERIA 
9.1. 
EFFICACY ASSESSMENT  
9.1.1. Primary endpoint 
Primary outcome will be the detection of the percentage of patients after 4 weeks of edoxaban 
treatment with complete thrombus resolution by TEE, evaluated with the following Probe 
angulations: 0°, 45°-to-60°, 90°. 
9.1.2. Secondary endpoint 
Secondary endpoints will be: 
• 
Absolute and percent variation of thrombus area at 4 weeks by TEE evaluation  (Probe 
angulations: 0°, 45-to-60°, 90°)  
• 
Time to electrical cardioversion (when applicable). 
 
9.2. 
SAFETY ASSESSMENT 
• 
Incidence of bleeding events at 4 weeks and after 8 weeks (telephone assessment) 
after the end of treatment 
• 
Incidence of any stroke or peripheral embolism at 4 weeks and after 8 weeks 
(telephone assessment) after the end of the treatment. 

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9.2.1. Definition of major bleeding 
Major bleeding will be defined as follows (11) and reported as SAEs or AEs as described in 
Section 11: 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, and/or 
3. Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading 
to transfusion of two or more units of whole blood or red cells. 
9.2.2. Non-major bleeding 
Clinically relevant non-major bleeding (12) will be defined as bleeding that did not fall under 
the category of major bleeding, but corresponded to any of the following: 
1. hematoma of 5 cm in longest diameter 
2. epistaxis or gingival bleeding that occurred in the absence of external factors and lasts 
≥5 minutes 
3. GI bleeding 
4. gross hematuria that is persistent after 24 hours of onset, and 
5. other bleeding that was assessed to be clinically significant by the investigator or sub-
investigator. 
Any bleeding event that did not meet major or clinically relevant non-major bleeding criteria 
will be categorized as a minor bleeding event. 
 
9.2.3. Stroke and thrombotic events 
Thrombotic events will be defined as and reported as SAEs or AEs, as described in section 11. 

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1. Ischemic stroke 
2. Transient ischemic attack (TIA) 
3. Deep vein thrombosis (with or without pulmonary embolism) 
4. Any other form of systemic embolism. 
9.2.4. Adverse Events 
At Inclusion, any concomitant disease will be reported on the CRF. At each further visit, the 
occurrence of adverse events (AEs) since the last visit will be based on the patient’s or patient 
parents’ spontaneous oral reporting, the investigator's non-leading questioning and his/her 
clinical evaluation. Any AE reported will be re-assessed by the investigator through 
complementary questioning, and noted in the medical file. All AEs will be reported on the CRF. 
 
9.3. 
COMPLIANCE 
The patient will be reminded to bring back, at each visits, any remaining tablets, boxes (used or 
unused). At the follow-up visit, the Investigator will record the number of supplied and 
remaining tablet in the CRF. 
Considering the duration of the study, compliance will be judged as: 
 Complete if ≥ 100% taken (28 tablets or more) 
 Adequate if ≥ 75% and < 100% taken (at test 21 tablets) 
 Non adequate if < 75% taken (less than 21 tablets). 
 
10. STUDY PROCEDURES 
Each patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form approved by the competent EC. Acceptance to participate 

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in the study will be subordinated to the signature of the informed consent. A copy will be keep 
by the patient. 
10.1. BASELINE VISIT 
A screening assessment can occur on the same day of the baseline visit or up to 7 days before 
it. The patient will be assessed for the following: 
 Collection of the signed informed consent 
  
Verification of inclusion/exclusion criteria 
 Collection of demographic data, including: date of birth (month and year), gender, 
weight, height (calculated BMI), and race 
 Medical history (with evaluation of CHA2DS2-VASC score and HAS-BLED scores) 
 Information regarding AF 
 Blood pressure, heart rate 
 ECG 
 Transthoracic echocardiogram (TTE) 
 Transesophageal echocardiogram (TEE) 
 
 Therapy: antithrombotic treatment and concomitant treatments (antihypertensives, 
heart failure and antiarrhythmic therapies, metabolic and anti-inflammatory, 
antithrombotic therapies for indications other than AF), and other selected drugs. 
 Complete blood count; assessment of liver and renal function. 
10.2. FOLLOW-UP (WEEK 4) 
After four weeks of treatment, the patient will be visited and assessed for the following: 
 Serious adverse events, including hospitalizations, life threatening events and death 
 Non-serious adverse events 
 Information regarding AF  
 Concomitant diseases (current, any change) 
 Adherence to the study treatment 

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 Therapy (current, any change) 
 Blood pressure, heart rate 
 ECG 
 Transthoracic echocardiogram (TTE) 
 Transesophageal echocardiogram (TEE) 
 Complete blood count; assessment of liver and renal function. 
10.3. FINAL TELEPHONE ASSESSMENT (WEEK 8) 
 Serious adverse events, including hospitalizations, life threatening events and death 
 Non-serious adverse events 
 The investigator will also complete the final study form. 
10.4. ASSESSMENTS AND PROCEDURES 
10.4.1. Stroke risk index 
The CHA2DS2-VASc (Cardiac failure, Hypertension, Age doubled, Diabetes, Stroke doubled, 
Vascular, Age, Sex) composite stroke risk index is based on a point system in which 2 points are 
assigned for age ≥75 years and for a history of stroke or TIA and 1 point each is assigned for a 
history of hypertension, diabetes, recent cardiac failure, vascular diseases, age <75 years, and 
female gender (13). 
10.4.2. Bleeding risk index 
HAS-BLED is a scoring system developed to assess the 1-year risk of major bleeding in patients 
with atrial fibrillation A calculated HAS-BLED score is between 0 and 9, and based on one point 
assigned to each of the following parameters (14): 
1. Hypertension: uncontrolled or >160 mmHg systolic) 
2. Abnormal renal function: Dialysis, transplant, Cr >2.6 mg/dL or >200 µmol/L 
3. Abnormal liver function: Cirrhosis or Bilirubin >2x ULN or AST/ALT/AP >3 x ULN 
4.  Stroke: Prior history of stroke 
5. Bleeding: Prior Major Bleeding or Predisposition to Bleeding 

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6. Labile INR: (Unstable/high INRs), Time in Therapeutic Range < 60% 
7. Elderly: Age > 65 years 
8. Prior Alcohol or Drug Usage History 
9. Medication Usage Predisposing to Bleeding: (Antiplatelet agents, NSAIDs). 
11. ADVERSE EVENTS: DEFINITION AND REPORTING 
11.1. ADVERSE EVENTS 
11.1.1. Definition of Adverse Events 
An adverse event is any adverse change from the patient's baseline condition, i.e. any subjective 
signs and symptoms, or change in a concomitant disease present at the Inclusion Visit 
considered related or not related to the treatment.  
This includes intercurrent signs, symptoms and illnesses that may occur during the course of 
the clinical study.  
 
11.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
 Mild: awareness of signs or symptoms, but easily tolerated 
 Moderate: uncomfortable enough to cause interference with usual activity 
 Severe: incapacity with inability to work or do usual activity 
 
11.1.3. Reporting of Adverse Events 
The records of adverse events in the CRF describe the nature (diagnosis, signs and symptoms), 
severity, onset date, stop date, outcome and actions taken, and the relationship to study 

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treatment (in the Investigator's opinion). It must be specified whether the event is serious or 
not. 
11.2. SERIOUS ADVERSE EVENTS (SAE) 
11.2.1. Definition 
A serious adverse event (SAE) includes, but is not necessarily restricted to any event which: 
 results in death (whatever may be the cause) 
 is life-threatening 
 results in persistent or significant disability/incapacity 
 requires the patient’s hospitalisation or prolongation of current hospitalisation. The 
following ill not be reported as a SAE: a) planned medical/surgical procedures decided 
or scheduled prior patient’s signature of the informed consent; b) preparation for a 
routine health assessment/procedure; c) administrative or social reasons (e.g., lack of 
housing, economic inadequacy, care-giver respite, family circumstances) 
 Is a congenital anomaly or birth defect. 
Other events such as cancer, and any additional adverse experience occurring during the study 
period, defined by the protocol as serious, or which the Investigator considers significant 
enough, or that suggest a significant hazard, contra-indications, side effect or precaution, must 
be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE. 
 
11.2.2. Reporting of SAE 
All serious adverse events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, must be recorded by the Investigator as soon as he/she 
is informed of the event. 
The Investigator must notify the Promoter about this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") reported in Appendix 17.2 of 

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the study protocol, with all the available information about the event to the Promoter's 
pharmacovigilance unit: 
 
Contact 
Number or address 
Instruction or comment 
e-mail 
Farmacia.ortona@asl2abruzzo.it 
(24 hours coverage) 
Please attach PDF scan of the SAE form 
Fax 
0859172356 
(24 hours coverage) 
If  not possible to send the report by e-mail 
Phone 
0859172202 
(business hours) 
Only if it is not possible to send a paper report 
 
11.2.3. Follow-up of SAE 
The Investigator must design a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up"), and collect the results of the carried-out examinations and 
the reports of hospitalization. 
Serious adverse events must be followed-up until resolution or stabilisation. 
 
11.2.4. SAE Occurring After the Study 
Because of the 4 week follow-up after the end of treatment, any SAE occurring after the end of 
the study last follow-up visit will not be notified to the Promoter. 
However, the Promoter must be notified of any event occurring at any time after the end of the 
study (last follow-up visit) for the patient who may be related to the study treatment in the 
Investigator's opinion. 

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12. DATA COLLECTION AND STUDY MONITORING 
12.1. DATA COLLECTION 
12.1.1. Case Report Form 
A paper Case Report Form (CRF) will be used to record all patient data required by the protocol. 
All the information included into the CRF will be recorded from source documents onto the CRF 
by an authorized person. A CRF must be completed for each patient who will have a signed 
informed consent. 
12.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. Documents, such as 
patients’ diaries or similar papers recorded by the patients will also be kept by the Investigator 
as source documents. 
Source documents, along with all other trial-related documents (copies of all "informed 
consent" forms, drug inventories and any correspondence related to the study) must be kept in 
the Investigator's file throughout the study, and then, stored for a period of at least 15 years or 
as per local legal requirements, whatever is the longest.  
12.2. STUDY MONITORING 
12.2.1. Monitoring visits 
On-site visits will be carried out by a CRA appointed by the Promoter at regular intervals 
throughout the study, according to the monitoring plan schedule. Additional visits and 
communication by telephone fax or meeting may be performed, if necessary. Any site visit 
performed by the Promoter's representatives will be recorded in the Investigator's study file. 
 

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12.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Promoter’s representatives (Study Manager, 
CRA and Auditors) have to be given a direct access to all source and study data to perform 
quality monitoring/audit, thus ensuring accuracy and completeness of data).  
 
Investigators are reminded that all Promoter’s representatives keep professional confidentiality 
with regards to the patient data. 
13. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerized database 
under the supervision of a Data Manager, according to the following procedures: 
13.1. DATA ENTRY 
All required data will be collected by the Investigator or an authorised designee (duly identified 
into the delegation task list) on the CRF, and entered in a computerized database.  
13.2. DATA CLEANING 
The designed Data Manager will define descriptions of both manual and electronic edit checks 
in the Data Validation Plan for reviewing and querying data. 
The designed Data Manager will review the data over the course of the study, in order to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making 
changes directly into the CRF. 

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13.3. DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded using the 
MedDRA dictionary (latest version in use), whereas concomitant medication will be coded using 
the WHO-ATC drug dictionary (latest version in use). 
13.4. DATABASE LOCK 
The validated database will be locked upon request of the designed Data Manager following 
the completion of all steps required, i.e.: data entry and check of all data, resolution of all 
queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation Committee.  
14. STATISTICAL ANALYSIS 
14.1. GENERAL CONSIDERATIONS 
 
The objective of this exploratory study is the estimation of the magnitude of the LA/LAA 
thrombus resolution after 4 weeks therapy with edoxaban. 
14.2. SAMPLE SIZE 
There are no previous studies conducted with edoxaban on atrial thrombus dissolution, and this 
is a pilot trial. For this reason, the sample size has beeen determined empirically, on the basis 
of case reports with similar products in this clinical conditions (6, 8-10, 15). 
However, if the proportion of patients with thrombus dissolution after 4 weeks of treatment  
will be 60%, which is compatible with the above-mentioned case reports, a sample size of 25 
produces a two-sided 95% confidence interval with range 39-79%. 

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The involvement of 6-8 sites implies an enrolment of an average of about 4 patient per site to 
be recruited in about 15 months. 
14.3. PROTOCOL DEVIATIONS 
Prior to the analysis, the Project Manager and Data Manager will review the protocol deviations 
and will classify them as either minor or major. A protocol deviation will be considered major 
when it is likely to bias significantly the treatment effect estimate based on the primary efficacy 
criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see Section 
14.4). 
A listing of all protocol deviations will be provided for all randomized patients, including the 
type (major/minor) of protocol deviations according to the decisions made by the members of 
the Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set, as defined in 
Section 14.4. 
14.4. DATA SETS ANALYSIS 
 
The following data sets will be analyzed:  
 The Full Analysis Set (FAS), composed of all patients having received at least one dose 
of the study treatment. This data set will be used to perform analyses of Safety and 
Efficacy.  
 The Per Protocol (PP) set, which is the subset of the Full Analysis Set composed of all 
patients without any major protocol deviation or other source of bias for primary criteria 
analyses and characterised by a treatment compliance ≥80%. 

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14.5. HANDLING OF DROPOUTS AND MISSING DATA 
14.5.1. Dropouts and Missing Data 
The number and percentage of patients who prematurely stopped the study treatment will be 
provided by treatment group for all treated patients (FAS). Patients who prematurely stopped 
the study drug will be further described, regarding their time to premature withdrawal and 
reasons for premature study drug discontinuation. 
No replacement of missing data will be performed. 
14.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Patient’s background, medical and surgical history, demographic data, disease characteristics 
and baseline efficacy criteria will be described on the FAS, by treatment group and overall: 
 Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values 
 Qualitative parameters will be described by treatment group and overall using 
frequencies. 
For each year, concomitant diseases, as well as medical and surgical histories, will be tabulated 
descriptively by treatment group and overall using the MedDRA codes of System Organ Classes 
and preferred terms. 
14.7. EFFICACY ANALYSIS  
14.7.1. Primary Criterion  
The primary outcome will be the detection of the percentage of patients, after 4 weeks of 
edoxaban treatment, with complete thrombus resolution by TEE, evaluated with the following 
probe angulations: 0°, 45°-to-60°, 90°. 

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As this is a single arm, open-label study, in principle, only a descriptive statistical analysis will 
be performed for the primary criterion. The primary analysis will be performed both on the FAS 
and the PP sets. Whenever appropriate, the statistical significance level will be 5%. 
 
14.7.2. Secondary Criteria 
Secondary endpoints will be: 
• 
Absolute and percent variation of thrombus area at 4 weeks by TEE evaluation  (probe 
angulations: 0°, 45-to-60°, 90°). 
• 
Time to electrical cardio-version (when applicable). 
 
Unless otherwise specified in the Statistical Analysis Plan, only a descriptive statistical analysis 
will be performed for the secondary criterion that will be carried out on the FAS and the PP 
sets. Whenever appropriate, the statistical significance level will be 5%. 
14.8. SAFETY ANALYSIS 
The Full Analysis Set will be used to perform all analyses of the safety criteria that will include: 
 Percentage of bleeding events at 4 weeks and after 8 weeks (telephone assessment) 
after the end of the treatment 
 Percentage of any stroke or peripheral embolism at 4 weeks and after 8 weeks 
(telephone assessment) after the end of the treatment 
 Percentage of any other safety related events (deaths, SAEs and AEs). 

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14.8.1. Adverse Events 
Any treatment emergent adverse events having been reported, after randomization, during the 
study for a given patient will be classified by preferred term and corresponding system organ 
class using the MedDRA terminology. 
Numbers and percentages of patient with at least one reported treatment emergency adverse 
event will be tabulated by treatment group in decreasing order for the arm: 
A. By system organ class 
B. By system organ class and preferred term 
C. By system organ class and preferred term, taking into consideration its most severe 
intensity 
D. By system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a 
given patient will only be counted once, and only their most severe intensity or most severe 
relationship to the study treatment will be tabulated. 
Moreover, serious adverse events will be described on an individual basis: treatment group, 
patient's code, sex and age, Investigator's reported term, preferred term, date of onset 
according to the date of the first study treatment administration, duration, action taken 
regarding the study treatment administration, use of a corrective treatment, outcome and 
relationship to the study treatment in the Investigator’s opinion. 
 
14.8.2. Concomitant treatments 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" (ATC) classification on the safety data set. 

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14.9. COMPLIANCE 
 
Compliance will be judged as: 
 
Complete if ≥ 100% tablets taken (28, or more) 
 
Adequate if ≥ 75% and <100% tablets taken (at least 21) 
 
Inadequate if < 75% tablets taken (less than 21). 
14.10. INTERIM ANALYSIS AND DATA MONITORING 
No formal interim statistical analysis will be performed. Anyway, this is an open label study and 
just descriptive statistics will be performed on an on-going base through the entire duration of 
the study.  
14.11. ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(2013) and subsequent amendments, and in accordance with the Good Clinical Practice 
Guidelined (CPMP/ICH/135/95). 
14.12. ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
This clinical trial was designed and will be conducted in accordance with the Italian Ministerial 
Decree 17 December 2004 governing the non-profit studies. 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee, whose procedures and 
operations meet the GCP and National Legal Requirements. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator), with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required is 
carried out by the Sponsor. 

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The active recruitment of patients will not start before the approval of the Ethics Committee 
and after the study is authorized by the Competent Authority or notified to the Competent 
Authority. 
14.13. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT FORM 
An information must be given to the patient before their decision to participate or abstain from 
participation. 
This information is based on the Declaration of Helsinki and the ICH GCP Guidelines. It must also 
describe the measures taken to safeguard patient’s privacy and protection of personal data, 
according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure.  
One copy of information and consent document is kept by the Investigator, and one copy is 
given to the patient. 
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to participate in the trial, an updated written informed consent must be submitted 
to the patient to confirm the agreement for continue participating. 
14.14. PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility, in accordance with both the applicable Italian law 
(Decreto Legislativo 2003-06-30 n. 196 and subsequent amendments) and the European 
Directive 95/46/CE. 

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14.15. INSURANCE POLICY 
15. THE SPONSOR, BEING RESPONSIBLE FOR THE CLINICAL STUDY, 
UNDERWRITES AN ADEQUATE INSURANCE POLICY WITH ACE EUROPEAN 
GROUP LTD, IN FAVOR OF SUBJECTS PARTICIPATING THIS CLINICAL TRIAL.  
THE INSURANCE CONTRACT WILL BE IN COMPLIANCE WITH THE LOCAL 
REGULATION AND HEALTH AUTHORITIES REQUIREMENTS.   
ADMINISTRATIVE PROCEDURES 
15.1. PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorization of 
the other party.  All changes to the protocol are subject to an amendment, which must be dated 
and signed by both parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees 
and Competent Authorities. 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions 
defined with the Sponsor. 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigators: 
 
Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, CD-ROM with pdf files, drug inventory, Ethics 
Committees and Sponsor correspondence pertaining to the study must be kept on file 
 
Retains all documents relating to the screening (consent and investigation results) of all 
subjects included in the trial or not 
 
Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on CRFs with those from source documents. 

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 
Authorizes direct access to source documents for monitoring, audits and inspections 
 
Retains the trial-related documents as strictly confidential at the Investigator’s site for at 
least 15 years or according to local requirements, whatever is the longest, after the 
completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the date of the last visit of the last patient undergoing the trial. Any change 
to this definition during the study, for whatever reason, must be notified as a substantial 
amendment. 
15.3.2. Early Study Termination 
15.3.2.1. Early Study Termination Decided by the Sponsor 
The Sponsor Fondazione Gabriele d’Annunzio - Chieti may discontinue the study at any 
time for any of the following reasons: 
 Lack of recruitment 
 Deviations from good clinical practice and/or regulations 
 Poor product safety/ lack of efficacy 
 New information that could jeopardise the patient’s safety 
 Stopping of the drug development. 
15.3.2.2. Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they considers that the 
conditions of authorization are not being met, or has doubts about the safety or 
scientific validity of the study. 

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15.4. AUDIT 
The Sponsor Fondazione Gabriele d’Annunzio  - Chieti is responsible for making sure that both 
his representatives (Study Manager, CRA, etc.) and the Investigator fulfil the requirements as 
specified by the GCP Guideline.  
An audit can be organized internally by the Sponsor and at the investigational site, where the 
CRFs are matched against source documents. All study documentation must be directly 
accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. Oral information about the audit results are given to the 
Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the 
study or after its completion to verify the conduct of the study and quality of the data. The 
Investigator must provide the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol, CRF, etc.) contain confidential information.  
Except if agreed to in writing with the Fondazione Gabriele d’Annunzio - Chieti, the investigators 
must hold such information confidential, and must not disclose it to others (except where 
required by Applicable Law). 
15.7. STUDY RESULTS PUBLICATION 
All the results of this study including data, reports, discoveries and inventions resulting from 
the study, are the property of the Sponsor Fondazione Gabriele d’Annunzio – Chieti, and have 
to be considered as confidential. 

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16. REFERENCES 
16.1. BIBLIOGRAPHY 
1. 
Camm J et al. Guidelines for the management of atrial fibrillation. The Task Force for the 
Management  of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart 
J 2010;31:2369-429 
2. 
Saeed M et al. Role of transesophageal echocardiography guided cardioversion in patients 
with atrial fibrillation, previous left atrial thrombus and effective anticoagulation. Int J 
Cardiol 2006;113:401-5 
3. 
Akdeniz B et al. Cardioversion under the guidance of transesophageal echochardiograhy 
in persistent  atrial fibrillation: results with low molecular weight heparin. Int J Cardiol 
2005;98:49-55 
4. 
Collins LJ et al. Cardioversion of Nonrheumatic Atrial Fibrillation Reduced 
Thromboembolic Complications With 4 Weeks of Precardioversion Anticoagulation Are 
Related to Atrial Thrombus Resolution. Circulation 1995;92:160-3  
5. 
Seidl K et al. Embolic events in patients with atrial fibrillation and effective 
anticoagulation: value of  transesophageal echocardiography to guide direct-current 
cardioversion. Final results of the Ludwigshafen  Observational Cardioversion Study. J Am 
Coll Cardiol 2002;39:1436-42 
6. 
Hammerstingl C et al. Resolution of giant left atrial appendage thrombus with 
rivaroxaban. Thromb Haemost  2013;109:583-4 
7. 
Giugliano RP et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in 
patients with atrial fibrillation. N Engl J Med 2013;369:2093-104 
8. 
Takasugi J, Yamagami H, Okata T, Toyoda K, Nagatsuka K. Dissolution of the left atrial 
appendage thrombus with rivaroxaban therapy. Cerebrovasc Dis. 2013;36(4):322-3 
9 
Vidal  A,  Vanerio  G:  Dabigatran  and  left  atrial  appendage  thrombus.  J  Thromb 
Thrombolysis 2012;  34:  545–547. 
10. 
Kaku B. Intra-cardiac thrombus resolution after anti-coagulation therapy with dabigatran 
in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy: a case report 
Journal of Medical Case Reports 2013. 7:238 
11 
Schulman S1, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and 
Standardization Committee of the International Society on Thrombosis and Haemostasis. 

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Definition of major bleeding in clinical investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4 
12 
Fuji T, Fujita S, Kawai Y, Nakamura M, Kimura T, Kiuchi Y, Abe K, Tachibana S. Safety and 
efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res. 2014 
Jun;133(6):1016-22 
13 
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for 
predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-
based approach: the Euro Heart Survey on atrial fibrillation. Chest 2010;137:263–272. 
14 
Pisters, Ron; Lane, D. A.; Nieuwlaat, R; De Vos, C. B.; Crijns, H. J.; Lip, G. Y. (2010). "A Novel 
User-Friendly Score (HAS-BLED) to Assess 1-Year Risk of Major Bleeding in Patients with 
Atrial Fibrillation". CHEST Journal 138 (5): 1093–100. 
15 
Saito S, Shindo S, Tsudaka S, Uchida K, Shirakawa M, Yoshimura S. Resolving Thrombus in 
the Left Atrial Appendage by Edoxaban Treatment after Acute Ischemic Stroke: Report of 
2 Cases. J Stroke Cerebrovasc Dis. 2016 Oct;25(10). 
 
 

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17. APPENDICES 
 
17.1. APPENDIX A - DECLARATION OF HELSINKI 
 
WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects 
 
Adopted by the 18th W MA General Assembly, Helsinki, Finland, June 1964 and amended by the: 29th W MA General Assembly, Tokyo, 
Japan, October 1975; 35th W MA General Assembly, Venice, Italy, October 1983; 41st W MA General Assembly, Hong Kong, 
September 1989; 48th W MA General Assembly, Somerset West, Republic of South Africa, October 1996; 52nd W MA General 
Assembly, Edinburgh, Scotland, October 2000; 53rd W MA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added); 55th W MA General Assembly, Tokyo, Japan, October 2004 (Note of clarification added); 59th W MA General 
Assembly, Seoul, Republic of Korea, October 2008; 64th W MA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.  
The World Medical Association (W MA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material and 
data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied 
with consideration of all other relevant paragraphs. 
2.  
Consistent with the mandate of the W MA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these principles. 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my 
first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the 
patient's best interest when providing medical care.” 
4.  
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are dedicated to the 
fulfilment of this duty. 
5.  
Medical progress is based on research that ultimately must include studies involving human subjects. 
6.  
The primary purpose of medical research involving human subjects is to understand the causes, development and 
effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continual y through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7.  
Medical research is subject to ethical standards that promote and ensure respect for all human subjects and 
protect their health and rights. 
8.  
While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence 
over the rights and interests of individual research subjects. 
9.  
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right 
to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or other health care professionals and 
never with the research subjects, even though they have given consent. 
10.  Physicians must consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11.  Medical research should be conducted in a manner that minimises possible harm to the environment. 

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12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and 
scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision 
of a competent and appropriately qualified physician or other health care professional. 
13.  Groups that are underrepresented in medical research should be provided appropriate access to participation in 
research. 
14.  Physicians who combine medical research with medical care should involve their patients in research only to the 
extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
15.  Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must 
be ensured. 
Risks, Burdens and Benefits 
16.  In medical practice and in medical research, most interventions involve risks and burdens. Medical research 
involving human subjects may only be conducted if the importance of the objective outweighs the risks and 
burdens to the research subjects. 
17.  All medical research involving human subjects must be preceded by careful assessment of predictable risks and 
burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them 
and to other individuals or groups affected by the condition under investigation. Measures to minimise the risks 
must be implemented. The risks must be continuously monitored, assessed and documented by the researcher. 
18.  Physicians may not be involved in a research study involving human subjects unless they are confident that the 
risks have been adequately assessed and can be satisfactorily managed. When the risks are found to outweigh the 
potential benefits or when there is conclusive proof of definitive outcomes, physicians must assess whether to 
continue, modify or immediately stop the study. 
Vulnerable Groups and Individuals 
19.  Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or 
of incurring additional harm. All vulnerable groups and individuals should receive specifically considered 
protection. 
20.  Medical research with a vulnerable group is only justified if the research is responsive to the health needs or 
priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group 
should stand to benefit from the knowledge, practices or interventions that result from the research. 
Scientiﬁc Requirements and Research Protocols 
21.  Medical research involving human subjects must conform to generally accepted scientific principles, be based on 
a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory 
and, as appropriate, animal experimentation. The welfare of animals used for research must be respected. 
22.  The design and performance of each research study involving human subjects must be clearly described and 
justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding 
provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the 
research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23.  The research protocol must be submitted for consideration, comment, guidance and approval to the concerned 
research ethics committee before the study begins. This committee must be transparent in its functioning, must 
be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must 

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take into consideration the laws and regulations of the country or countries in which the research is to be 
performed as well as applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to the 
protocol may be made without consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the study’s findings and 
conclusions. 
Privacy and Confidentiality 
24.  Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal 
information. 
Informed Consent 
25.  Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no individual capable of giving 
informed consent may be enrolled in a research study unless he or she freely agrees. 
26.  In medical research involving human subjects capable of giving informed consent, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed 
of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another appropriately 
qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If 
the consent cannot be expressed in writing, the non-written consent must be formal y documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome and results 
of the study. 
27.  When seeking informed consent for participation in a research study the physician must be particularly cautious if 
the potential subject is in a dependent relationship with the physician or may consent under duress. In such 
situations the informed consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
28.  For a potential research subject who is incapable of giving informed consent, the physician must seek informed 
consent from the legal y authorised representative. These individuals must not be included in a research study that 
has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the 
potential subject, the research cannot instead be performed with persons capable of providing informed consent, 
and the research entails only minimal risk and minimal burden. 
29.  When a potential research subject who is deemed incapable of giving informed consent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the consent of the legal 
y authorised representative. The potential subject’s dissent should be respected. 
30.  Research involving subjects who are physical y or mental y incapable of giving consent, for example, unconscious 
patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary 
characteristic of the research group. In such circumstances the physician must seek informed consent from the 
legal y authorised representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be obtained as 
soon as possible from the subject or a legal y authorised representative. 

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31.  The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a 
patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect 
the patient- physician relationship. 
32.  For medical research using identifiable human material or data, such as research on material or data contained in 
biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. 
There may be exceptional situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and approval of a research ethics 
committee. 
Use of placebo 
33.  The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven 
intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention less effective 
than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of 
an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.  In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-
trial access for all participants who still need an intervention identified as beneficial in the trial. This information 
must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.  Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36.  Researchers, authors, sponsors, editors and publishers al have ethical obligations with regard to the publication 
and dissemination of the results of research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their reports. Al parties 
should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results 
must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts 
of interest must be declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.  In the treatment of an individual patient, where proven interventions do not exist or other known interventions 
have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a 
legally authorised representative, may use an unproven intervention if in the physician's judgement it offers hope 
of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the 
object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 

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17.2. APPENDIX B - SAE FORM 
 
 
NOTIFICATION OF SERIOUS ADVERSE EVENT (SAE) 
TO BE TRANSMITTED BY FAX WITHIN 24 H TO ___________________ 
 
Site N°: |__|__| 
Patient N°|__|__| 
REPORT: INITIAL |__|   FOLLOW UP |__|   N°_____ 
 
PATIENT CHARACTERISTIC 
Birth date |__|__| |__|__| |__|__| (dd/mm/yy) 
 
Gender  
M  |__| 
F |__| 
Height |__|__|__| cm 
  
 
Weight |__|__|.|__| kg 
 
 
 
SERIOUS ADVERSE EVENT: 
 
___________________________________________________________________________________ 
 
Onset date: |__|__| |__|__| |__|__| Site staff awareness date:  |__|__| |__|__||__|__| 
 
dd/mm/yy 
dd/mm/yy 
 
NARRATIVE: 
……………………………………………………………………………………………………………………………………………………………… 
……………………………………………………………………………………………………………………………………………………………… 
……………………………………………………………………………………………………………………………………………………………… 
……………………………………………………………………………………………………………………………………………………………… 
……………………………………………………………………………………………………………………………………………………………… 
……………………………………………………………………………………………………………………………………………………………… 
……………………………………………………………………………………………………………………………………………………………… 
 
 
SEVERITY CRITERIA: 
|__| Resulted in Death on date: |__|__| |__|__| |__|__| ( dd/mm/yy) 
|__|Life-threatening 
|__|Hospitalization / prolongation of hospitalization 
|__|Persistent /significant disability/ incapacity 
|__| Birth defect or congenital abnormality 
|__| Any other serious clinical or laboratory event 
In case of death, has an autopsy been conducted? |__| NO 
|__| YES (please enclose the report) 
 
 
OUTCOME: 
|__|Resolved        Date of recovery: 
|__|__| |__|__| |__|__| ( dd/mm/yy) 
|__|Resolved with sequelae 
|__|__| |__|__| |__|__|  dd/mm/yy 
|__|Improved 
|__|Unchanged 
|__|Worsened 
|__|Death 

Fondazione Gabriele d’Annuzio - Chieti  
Confidential  
Protocol EDO-SP-01-2015 
 
Clinical Study Protocol - Version 4.0 -18 Sept 2017 
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MEASURES TAKEN FOLLOWING THE SAE: 
 
Study treatment: 
|__|None  
|__| Temporarily discontinued specify the n° of days: |__|__| 
|__| Definitively discontinued (specify end of treatment date |__|__| |__|__| |__|__| dd/mm/yy ) 
|__| Dose reduced (specify the new dose____________and start date |__|__| |__|__| |__|__|  
|__| Not Applicable 
 
The event led to: 
|__| Prescription of corrective treatments. Specify names and dosage:  
 
______________________________________________________________________________ 
 
|__| Discontinuation of concomitant treatments. Specify names and dosage: 
 
______________________________________________________________________________ 
 
|__| Other, specify: 
 
______________________________________________________________________________ 
 
 
FOLLOW – UP: 
 
The SAE is closed after the dosage modification or discontinuation of the study treatment/suspect 
concomitant? 
|__|NO 
|__|YES   
|__|NA 
 
The SAE is occurred again after the new dispensing? 
|__|NO 
|__|YES   
|__|NA 
 
 
THE SAE IN RELATION TO THE TRIAL: 
 
Study treatment: ___________________ 
Treatment number: __________________________ 
Date of first study treatment administration: |__|__| |__|__| |__|__| dd/mm/yy 
Date of last study treatment administration:         |__|__| |__|__| |__|__| dd/mm/yy 
Daily dose: _________________________  
Frequency: ________________________________  
Formulation: ________________________ Route of administration: ______________________ 
 
Was the blind open? 
|__|NO 
|__|YES   
|__|NA 
 
If yes, or if this is an open study, drug administered 
|__| ______________________ 
 
 

Fondazione Gabriele d’Annuzio - Chieti  
Confidential  
Protocol EDO-SP-01-2015 
 
Clinical Study Protocol - Version 4.0 -18 Sept 2017 
50/51 
 
 
 
RELATIONSHIP BETWEEN THE SAE AND THE STUDY TREATMENT 
|__|Related 
|__|Unrelated 
|__|Unknown 
 
 
Is there a reasonable possibility that the event is related to  a concomitant drug ? 
|__| NO  
|__|YES  If yes specify:________________________ 
 
Is there a reasonable possibility that the event is related to a Clinical Trial Procedure? 
|__| NO  
|__|YES  If yes specify:________________________ 
 
 
CONCOMITANT TREATMENTS (EXCEPT THE TREATMENTS GIVEN FOR THE SAE) 
Include drugs taken at the moment of the event onset and in the last two weeks. If more space is need 
, use additional copies of this page  |__| YES 
 
TREATMENT 
START DATE 
STOP DATE 
Ongoing. 
ROUTE /DOSE/ FREQ. ADMINISTR. 
 
______________ ___________ 
__________ 
____ 
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______________ ___________ 
__________ 
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______________ ___________ 
__________ 
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______________ ___________ 
__________ 
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______________ ___________ 
__________ 
____ 
______________________________ 
______________ ___________ 
__________ 
____ 
______________________________ 
 
 
RELEVANT MEDICAL HISTORY 
If more space is need, use additional copies of this page  |__| YES 
 
DISEASE 
START DATE 
STOP DATE 
Ongoing. 
PERTINENT DETAILS (*) 
 
______________ ___________ 
__________ 
____ 
______________________________ 
______________ ___________ 
__________ 
____ 
______________________________ 
______________ ___________ 
__________ 
____ 
______________________________ 
______________ ___________ 
__________ 
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______________________________ 
______________ ___________ 
__________ 
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______________ ___________ 
__________ 
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______________ ___________ 
__________ 
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______________________________ 
______________ ___________ 
__________ 
____ 
______________________________ 
______________ ___________ 
__________ 
____ 
______________________________ 
______________ ___________ 
__________ 
____ 
______________________________ 

Fondazione Gabriele d’Annuzio - Chieti  
Confidential  
Protocol EDO-SP-01-2015 
 
Clinical Study Protocol - Version 4.0 -18 Sept 2017 
51/51 
 
(*) INCLUDE SURGICAL PROCEDURES AND DATES 
OTHER EXAMS    |__| NO  
|__| YES 
List only relevant diagnostic and confirmatory tests for event  
 
TEST 
DATE 
OUTCOME 
 
________________________ 
______________ 
_______________________________ 
 
 
REPORTER COMMENTS 
Report  date: 
  |__|__| |__|__| |__|__| dd/mm/yy 
The event was reported: 
|__| Spontaneously 
|__| After request 
|__| After source document verification 
 
 
Reporter: 
______________________        _____________           ____________________________ 
Print Name                                        Position                                     Signature 
 
Investigator’s name________________________  
 
Investigator’s signature___________________________ 
 
Comments: 
____________________________________________________________________________________
____________________________________________________________________________________
____________________________________________________________________________________
____________________________________________________________________________________
_________________________________________________________________________________